CN101822666A - Application of benzoyl silibinin for preparing medicaments for treating viral hepatitis B - Google Patents
Application of benzoyl silibinin for preparing medicaments for treating viral hepatitis B Download PDFInfo
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Abstract
The invention relates to application of benzoyl silibinin for preparing medicaments for treating viral hepatitis B, in particular to application of 23-bit 3,4-dimethoxy-benzoyl substituted silibinin ester or medicinal salts thereof for preparing medicaments which are used for eliminating Hepatitis B virus surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and inhibiting HBV (Hepatitis B Virus) DNA replication. The compound plays an extremely remarkable role in inhibiting HBsAg and HBeAg activities, and the strengths for eliminating the HBsAg and the HBeAg under the concentration of 20 micrograms/ml in the compound are respectively 93.3 percent and 91.2 percent; meanwhile, the compound displays more than 99 percent of inhibition ratio to HBV DNA under the concentration of 20 micrograms/ml and has 23 percent of inhibition ratio higher than that of positive control medicine Lamivudine and 2.6 times higher than that of Alpha-interferon. Results indicate the application of flavone lignans and medicinal salts which are expectedly used for preparing non-nucleoside medicaments for eliminating the HBsAg and the HBeAg, 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 kind of 23 3, the silybin ester that 4-dimethoxy benzoyl replaces or its officinal salt are used to prepare the purposes that reduces hepatitis B virus surface antigen HBsAg and hepatitis B virus e antigen HBeAg, inhibition HBV dna replication dna or treat hepatitis b virus infected disease medicament.This flavanolignan has and suppresses HBsAg and HBeAg activity extremely significantly, its intensity of removing HBsAg and HBeAg is respectively 93.3% and 91.2% under 20 mcg/ml concentration, surpasses 5.8 times and 5.4 times of positive control medicines (alpha-interferons of 10000 units per ml) respectively; More infusively be: it demonstrates suppression ratio greater than 99% to HBV DNA when this concentration, exceeds positive control medicine lamivudine 23%, exceeds 2.6 times of alpha-interferons.Above pharmacodynamic result shows that this flavanolignan or its officinal salt can expect the purposes that is used to prepare the hepatitis b virus infected disease non-nucleoside of the treatment medicine of removing HBsAg and HBeAg, inhibition HBV dna replication dna.
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.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, 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 surface antigen (HBsAg) is the coat protein of hepatitis B virus, and the HBsAg positive is a goldstandard of judging that HBV infects.The HBsAg 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 hepatitis B virus core antigen HBeAg, the HBV DNA positive and DNA polymerase, thereby infectiousness is strong more.Therefore, suppress the secretion of HBsAg and duplicate and be an important target in the research and development anti-hepatic-B virus medicine and 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 obtain HBsAg before liver cirrhosis, then its liver cirrhosis and hepatocarcinoma incidence rate will reduce by 60 times.All HBsAg 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.
According to European liver EASD in 2008 annual meeting: Polyethylene Glycol Intederon Alpha-2a treatment CHB patient 48 week back drug withdrawals, 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 1,2,3,4 to be only be 0%, 0%, 0% and 3% after drug withdrawal to the HBsAg clearance rate with the lamivudine person separately.Thereby this interferon is considered to treat the negative CHB patient's optimal treatment of HBeAg and selects, and the medicine that HBsAg can be efficiently removed in visible discovery has important social and economic benefit.
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.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.In like manner, suppress the secretion of HBeAg and duplicate and also be 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 medicine active or that express 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.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.Though, the research that 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, and 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 HBV DNA, ALT and liver histological after the drug withdrawal; The 3rd, comparatively significantly ill effect, for example kidney injury, baby's teratogenesis etc. that the life-time service nucleoside medicine occurs.Headache is the most: virus is drug-fast curative effect 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.
This biological engineering class antiviral drugs that derives from human leukocyte of interferon (α, beta-interferon and recombinant interferon class etc.) 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 HBsAg 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 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 for the treatment of chronic viral hepatitis B virus clinically, but its side effect and untoward reaction report is more, total effective rate is not high, cost an arm and a leg, patient economy burden is big, thereby causes and be difficult to clinically be extensive use of; And it is inapplicable to the decompensated cirrhosis patient.
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, 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.Therefore advocate now that 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 the strategy of decision long-term prescription replys with the virusology that obtains persistence, reach and continue the purpose that virus suppresses; According to the virological situation of replying of HBV DNA, create serological switching foundation of HBeAg and condition, to reach 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 HBVDNA 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, to the observation of curative effect, assessment hepatitis B prognosis and drug resistance danger are all had bigger directive function.Therefore, 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 HBsAg and 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.And 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 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, the chemical compound that suppresses the HBV dna replication dna, thus illustrating to filter out from natural product and synthesis of derivatives thereof to reduce HBsAg or HBeAg, 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.; 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 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 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); Inhibition HBsAg, HBeAg that the inventor has delivered 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), 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., 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 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.Its representative compounds surely belongs to flavanolignan's silibinin, and flavone lignin compound belongs to weedtree quality class, is a class natural product of and a part flavone be combined into plain by a part phenylpropyl alcohol.Herba Silybi mariani is extensive use clinically, its commodity Legalon by name on market
TMGrand or the Flavobion of sharp liver
TMSilibinin 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 K.Flora etc., Am.J.Gastroenterol, 1998,93,139-143; R.Saller etc., Drugs, 2001,61 (14), 2035-2063; R.
Deng, Curr.Med.Chem.2007,14,315-338; Z.
Deng, Phytother.Res.2003,17,524-530; R.
Deng, Bioorg.Med.Chem.2004,12,5677-5687; Z.Varga etc., Phytothe.Res.2001,15,608-612.R.P.Singh 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 andexamination of neuron protective properties of alkenylated and amidateddehydro-silybin derivatives ", Journal of Medicmal 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 ofNovel Silybin Analogues ", Journal of Enzyme Inhibitionand Medicinal Chemistry, 2006,21 (4), 399-404; Or the like).In the above-mentioned article of inventor report, flavanolignan's compounds of A ring, B ring, E ring and 23 replacements of a plurality of series that design and synthesize out through the inventor all demonstrates activity, antioxidant activity and the protection PC12 cell activity of the potent DPPH of catching free radical and ultra-oxygen anion free radical.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 it appears in the newspapers less relatively in the document of antiviral therapy aspect, and the compounds for treating DNA of flavanolignan viroid infection especially its new purposes that is used for anti-hepatitis virus aspect (comprising inhibition HBsAg or HBeAg, inhibition HBV dna replication dna) is effectively developed as yet.(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.
(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, do 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.
To sum up, seek the reactive compound in anti-hepatitis virus field from flavanolignan, 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 the lead compound challenge that forefathers did not attempt especially of removing HBsAg or HBeAg, inhibition HBV dna replication dna.In order to explore this field, we have prepared and silibinin structure a kind of new flavanolignan's derivant of difference to some extent, also i.e. substituted benzoic acid in 23 connections of former silibinin, whole molecular conjugation scope and conjugation intensity have been prolonged, also prolonged simultaneously the replacement length of former 23 hydroxyl modules, introduce new hydrogen bond receptor or donor simultaneously, 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.In the hope of finding the activity and even the lead compound of unusual removing HBsAg or HBeAg, inhibition HBV dna replication dna, finish the present invention in view of the above.
Summary of the invention
Order of the present invention is to find to reduce flavanolignan's lead compound of HBsAg or HBeAg, inhibition HBV dna replication dna, thereby it is developed further into the novelty medicine with the treatment CHB that can remove HBsAg or HBeAg, inhibition HBV dna replication dna effect.
The purpose of this invention is to provide 23 3 shown in the formula (1), the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces or its officinal salt are used for the new purposes that preparation is removed HBsAg or HBeAg, inhibition HBV dna replication dna, treated the hepatitis B medicine.
The name of formula (1) chemical compound is called: (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester.
The present invention also provides 23 3 shown in a kind of preparation formula (1); the method of the silybin esters flavonol lignin chemical compound that 4-dimethoxy benzoyl replaces; it is characterized in that: with commercially available or homemade silibinin and 3; the 4-dimethoxybenzoic acid carries out condensation reaction and gets in the presence of triphenyl phosphorus and diethyl azodiformate.
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 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.
Shown in the above-mentioned formula (1) 23 3, the silibinin ester compounds that 4-dimethoxy benzoyl replaces 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, conjugated degree, electrical distribution center all have obviously different with silibinin; And chemical compound (1) molecular weight ratio silibinin has increased 164 mass units.Above-mentioned characteristics determined chemical compound shown in the formula (1) three-dimensional conformation and HBsAg or or the ligand-receptor that combines of the 3d space structure of HBeAg and even HBVDNA all can produce bigger change in conjunction with complex form and combination (binding site and binding pattern, its in conjunction with free energy etc.), thereby may beyond thought effect be 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, have tested it simultaneously to B-mode HBsAg, the HBeAg of HepG2.2.15 emiocytosis and the inhibition activity that HBVDNA is duplicated.Result of the test is found: synthetic 23 3 of obtaining among the present invention, the silybin ester that 4-dimethoxy benzoyl replaces i.e. (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] that the HBsAg of HepG2.2.15 emiocytosis and HBeAg are had a significant inhibition is active for methyl ester, its intensity of removing HBsAg and HBeAg is respectively 93.3% and 91.2% under 20 mcg/ml concentration, surpasses 5.8 times and 5.4 times of positive control medicines (alpha-interferons of 10000 units per ml) respectively; More infusively be: it demonstrates suppression ratio greater than 99% to HBV DNA when 20 mcg/ml concentration, exceeds positive control medicine lamivudine 23%, exceeds 2.6 times of alpha-interferons.More than all formula (1) chemical compound beyond thought anti-HBV effect is arranged, thereby can expect medicine as the treatment hepatitis B of removing HBsAg or HBeAg, inhibition HBV dna replication dna.
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 HBsAg, HBeAg and the potent inhibition of HBV DNA, 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, found the activity of significant inhibition HBeAg again, found that also it has the inhibition HBV dna replication dna activity of extremely strong effect; The lead compound that is expected to become potent removing HBsAg or HBeAg, inhibition HBV dna replication dna and treats the non-nucleoside medicine of CHB.
Usefulness of the present invention is: 23 3 shown in the discoverable type (1) first, the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces has the effect of removing HBsAg or HBeAg, inhibition HBV dna replication dna, and it becomes treatment hepatitis B virus original new drug in the patent medicine potentiality aspect the control hepatitis B virus for exploitation; Provide new material base at the non-nucleoside original new drug of removing hbs antigen HBsAg or hepatitis B virus e antigen HBeAg, inhibition HBV dna replication dna, had potential huge social benefit and economic benefit.The present invention's characteristics again is: the synthetic starting material convenient sources of formula (1) chemical compound is easy to get, and synthetic method is simple, and cost is low, pollutes for a short time, is beneficial to the large-scale production under the energy-saving and emission-reduction condition, and industrialization prospect is very clear and definite.
The specific embodiment
The inventor is by chemosynthesis; and by multiple chromatography means purification obtain this can potent inhibition hepatitis B HBsAg and the secretion of HBeAg can effectively suppress the HBV dna replication dna again active one 23 3; the silybin ester flavonolignan class reactive compound that 4-dimethoxy benzoyl replaces is derived 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 hepatitis B HBsAg of HepG2.2.15 emiocytosis and secretion and the duplicating of HBV DNA of HBeAg are had significant inhibitory effect, point out this chemical compound to have drug safety, potent removing HBsAg or HBeAg, reach and suppress HBV dna replication dna characteristics of high efficiency.Therefore, according to the inventor's research, the flavanolignan's chemical compound shown in the formula (1) can be used to prepare the non-nucleoside medicine of treatment 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 HBsAg, 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.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.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 (±)-3, the preparation of 4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester
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 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.
1.2 the preparation of formula (1) chemical compound:
In exsiccant reaction bulb, add 1 gram silibinin (available from Liaoning Panjin lucky chance pharmaceutcal corporation, Ltd, or use this chamber preparation person voluntarily, HPLC detects purity 98%), 0.72 restrain 3,4-dimethoxybenzoic acid and 1.6 gram triphenylphosphines, with 20 milliliters of anhydrous tetrahydro furan dissolvings, add 1 gram diethyl azodiformate, add the back in stirring at room 10 hours, distilling under reduced pressure removes and desolvates, and adds 5 milliliters of chloroforms, remove by filter white solid, mother solution gets buff powder 0.57 gram, yield 42.5% through column chromatography.R
f(chloroform: ethyl acetate: formic acid=50: 1: 0.25)=0.19, proton nmr spectra
1H NMR (400MHz, deuterochloroform) δ: 3.81 (unimodal, 3H, OCH
3), 3.93 (unimodal, 3H, OCH
3), 3.97 (unimodal, 3H, OCH
3), 4.25 (multiplet, 1H, H-23a), 4.36 (multiplet, 1H, H-10), 4.55 (multiplet, 2H, H-3, H-23b), 4.99 (bimodal, J=12.0Hz, 1H, H-2), 5.00 is (bimodal, J=8.0Hz, 1H, H-11), 5.98 (unimodal, 1H, H-6), 6.00 (unimodal, 1H, H-8), 6.86～7.65 (multiplets, 10H, Ar-H), 11.20 (unimodal, 1H, 5-OH); Electrospray Mass Spectrometry ESI-MS:m/z 645[M-H]
+
Embodiment 2:Formula (1) chemical compound 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 growth of HepG2.2.15 cell and HBsAg:
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 formula (1) chemical compound 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.
Mensuration formula (1) chemical compound is to the inhibitory action of hbs antigen (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 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 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, and formula (1) chemical compound has the effect of significant 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 is 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 (±)-3 shown in the formula (1), 4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester has significant inhibitory effect to the hbs antigen (HBsAg) of HepG2.2.15 emiocytosis, its intensity of removing HBsAg is 93.3% under 20 mcg/ml concentration, surpasses 5.8 times of positive control medicines 2 (alpha-interferons of 10000 units per ml); More surpass 8.2 times of positive control 1 lamivudines.As seen there is very strong inhibition viral secretory surface antigen activity in this flavanolignan.
It is the state of approaching healing clinically 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:Formula (1) chemical compound 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 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 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).
3.4 experimental result: experimental result is as shown in table 2, formula (1) chemical compound (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester demonstrates the effect that suppresses hepatitis B e antigen (HBeAg) very significantly.Its growth to the HepG2.2.15 cell does not have obvious inhibitory action, reaches 91.2% 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 HBeAg is suppressed activity is zero; Positive control 2 is an alpha-interferon only has 16.9% inhibition activity to HBeAg the 8th day test concentrations the highest when (10000 units per ml).
Table 2. sample is to the excretory hepatitis B e antigen of HepG2.2.15 (HBeAg) suppression ratio (%)
3.5 presentation of results: its growth to the HepG2.2.15 cell of the flavanolignan's chemical compound shown in the formula (1) does not have obvious inhibitory action, but the hepatitis B e antigen HBeAg to HepG2.2.15 emiocytosis has significant inhibitory effect, it suppressed activity and reaches 91.2% in the time of the 8th day, surpass 5.4 times of positive control medicines 2 (alpha-interferons of 10000 units per ml); Simultaneously, more surpass demonstration and suppress active positive control 1 lamivudine.As seen this flavanolignan has and suppresses hepatitis B virus secretion HBeAg activity very significantly, 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 (deoxyribonucleic acid) (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 (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).
4.4 experimental result: experimental result illustrates as shown in table 3, and flavanolignan's formula (1) chemical compound has the effect of potent inhibition hepatitis B virus DNA replication.
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 (±)-3 shown in the formula (1), 4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester has very potent inhibitory action to duplicating of hepatitis B virus DNA (deoxyribonucleic acid) (HBV DNA), infusively be: it suppresses active in 99% to duplicating of HBV DNA when higher dosage (20 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), therefore this flavanolignan's chemical compound belongs to extremely significantly effectively non-nucleoside inhibition hepatitis B virus natural product, it suppresses activity to duplicating of HBV DNA and exceeds positive control medicine lamivudine 23%, exceed 2.6 times of alpha-interferons, reach the lead compound standard.Be worth very much further paying close attention to and further investigation, and can expect these 23 3, silybin ester that 4-dimethoxy benzoyl replaces or the further optimized development of its officinal salt are 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 entering claim of the present invention and its equivalent scope, practical application of the present invention comprises all general variations, cooperates, or improves.
Claims (4)
1. have 23 3 of structure shown in the formula (1), the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces or its officinal salt are used for the purposes of preparation treatment hepatitis B medicine;
The name of formula (1) chemical compound is called: (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester.
2. have 23 3 of structure shown in the formula (1), the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces or its officinal salt are used for the purposes that preparation reduces hepatitis B virus surface antigen HBsAg medicine;
The name of formula (1) chemical compound is called: (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester.
3. have 23 3 of structure shown in the formula (1), the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces or its officinal salt 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: (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester.
4. have 23 3 of structure shown in the formula (1), the silybin ester flavonolignan that 4-dimethoxy benzoyl replaces or its officinal salt are used for the purposes that preparation suppresses hepatitis B virus DNA (deoxyribonucleic acid) HBV dna replication dna medicine;
The name of formula (1) chemical compound is called: (±)-3,4-dimethoxybenzoic acid [3-(4-hydroxy 3-methoxybenzene base)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxygen-1-.alpha.-5:6-benzopyran-2)-2,3-dihydro-1,4-benzodioxane-2] methyl ester.
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| CN104744447A (en) * | 2013-12-31 | 2015-07-01 | 天士力制药集团股份有限公司 | Silibinin rosmarinate as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990484A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | Silybin esters derivatives and preparation and use thereof |
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| CN104744447A (en) * | 2013-12-31 | 2015-07-01 | 天士力制药集团股份有限公司 | Silibinin rosmarinate as well as preparation method and application thereof |
| CN104744447B (en) * | 2013-12-31 | 2017-12-26 | 天士力制药集团股份有限公司 | Legalon rosemary acid esters and its production and use |
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