CN101225087A - Coumarether compound and use of its composition - Google Patents
Coumarether compound and use of its composition Download PDFInfo
- Publication number
- CN101225087A CN101225087A CNA2007100364582A CN200710036458A CN101225087A CN 101225087 A CN101225087 A CN 101225087A CN A2007100364582 A CNA2007100364582 A CN A2007100364582A CN 200710036458 A CN200710036458 A CN 200710036458A CN 101225087 A CN101225087 A CN 101225087A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- hepatitis
- hydroxyl
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a coumaric grass ethers extracted from compositae plants, or a salt or an ester accepted in pharmacy, or the application of the plant extracts of the compound for the preparation of medicine for curing autoimmune liver disease and viral hepatitis. As shown by the vitro and vivo experiments to the animal body, the coumaric grass ethers extracted from compositae plants, or a salt or an ester accepted in pharmacy has the advantages of effective therapy and improvement of the symptoms of autoimmune liver disease and viral hepatitis.
Description
Technical field
The present invention relates to plant milk extract, relate in particular to a kind of Coumarether compound that from feverfew, extracts, perhaps contain the purposes of the pharmaceutical composition of this compound.
Background technology
Yerbadetajo Herb is traditional simply Chinese medicinal materials, is the herb of feverfew Eclipta prostrata (Eclipta prostrata Linn.), and the beginning is stated from Tang Materia Medica.The traditional Chinese medical science is thought the sweet acid of Yerbadetajo Herb property, cold, goes into liver, kidney channel, has that nourishing liver is enriched blood, the effect of cooling blood for hemostasis, cures mainly haematemesis, hemoptysis, early whitening of beard and hair, stranguria with turbid discharge, is with inferior disease.
It is reported that the Yerbadetajo Herb herb contains saponin, flavones, ecliptine (Ecliptine), tannin, VITAMIN, nicotine and multiple thiophene compound etc.; Leaf contains Coumarether compound, as Wedelolactone (Wedelolactone), demethylwedelolactone and demethylwedelolactone-7-glycoside.
1956, Govindachari etc. isolated Coumarether composition Wedelolactone (wedelolactone) first from Wedelia calendulacea, and its structure is:
(Chemical Examination of Wedelia Calendulacea，Part I，Structureof Wedelolactone.Govindachari，et al.Journal of the Chemical Society，1956，629-632；Chemical Investigation of Wedelia Calendulacea，Part II，The Position of the Methoxyl Group in Wedelolactone.Govindachari，et al.Journal of the Chemical Society，1957，545-547)。
Thereafter Bhargava etc. isolates demethyl wedelolactone (demethylwedelolactone) from Herba Ecliptae (Eclipta alba), and structural formula is:
(Isolation of desmethylwedelolactone and its glucoside from Ecliptaalba.Bhargava KK.et al.Indian J Chem，1970，8(7)：664-665)。
Li CC. etc. and United States Patent (USP) 6,552,071 disclose structure and synthetic method (Total synthesis of wedelolactone.Li CC.et al.J Org Chem, 2003,68 (22): 8500-8504 of such compound derivatives; Methods for treating cell death diseases andinflammation.Yuan, et al.United States Patent 6,552,071).
Modern pharmacology studies show that Yerbadetajo Herb has the effect of aspects such as hemostasis, immunomodulatory, expansion blood vessel, antimutagenic, anti-inflammatory.There are some researches show that Yerbadetajo Herb has stronger immune dual regulation.The ethyl acetate extract of Yerbadetajo Herb is cell-mediated cellullar immunologic response, the antagonism atrophy of immune organ of T of the low mouse of raise immunity significantly, also can significantly improve the ratio of serum hemolysin level and periphery blood T lymphocyte CD4 subgroup; But for the normal mouse of immunologic function, the ethyl acetate extract of Yerbadetajo Herb then can significantly suppress the cell-mediated cellullar immunologic response of its T (immunosuppressive action of Yerbadetajo Herb. Qin Hua, Liu Mei, Liu Xueying, Bao Guolin. the Shaanxi traditional Chinese medical science, 2002,23 (1): 73; Yerbadetajo Herb ethyl acetate total extract is to the immunosuppressed mice Immune Effects. Liu Xueying, Wang Qingwei, Zhao Yueping, Jiang Yongpei. and Chinese patent medicine, 2001,23 (1): 43-45; Yerbadetajo Herb ethyl acetate total extract is to the adjusting of T lymphocyte function. Liu Xueying, Zhao Yueping, Jiang Yongpei, soup seapeak. and The Fourth Military Medical University's journal, 2001,22 (8): 754-756).Also there are some researches show, the Yerbadetajo Herb water decoction can resist the immunologic injury that endoxan causes, the inhibition thymocyte apoptosis (Yerbadetajo Herb is to the regulating effect of mouse chest cell apoptosis. the scape brightness, Bai Xiuzhen, Yang Xuedong, Guo Yuncai, Li Jian. number reason medicine and pharmacology magazine, 2005,18 (4): 318-320).
In addition, domestic and international many pieces of bibliographical information Yerbadetajo Herbs have stronger liver provide protection.People such as Bupinder Singh pass through sherwood oil, benzene, acetone and 50% ethanol extraction of research Yerbadetajo Herb to the toxic liver provide protection of tetracol phenixin; find wherein with the most remarkable (the liver provide protection .Bupinder Singh of Yerbadetajo Herb of the liver provide protection of 50% ethanol extraction; Deng. foreign medical science traditional Chinese medicine fascicle; 1991,13 (6): 29).People such as Li Chunyang studies show that; the acute liver damage that the ethyl acetate extract Abensanil of Yerbadetajo Herb brings out has the better protecting effect; can obviously suppress liver injury mouse sALT, sAST rising (Herba Ecliptae extract is to the influence of liver provide protection. Li Chunyang; Bai Xiuzhen; Yang Xuedong. number reason medicine and pharmacology magazine; 2004,17 (3): 249-250).Have bibliographical information to think, the chemical ingredients that the Chinese medicine Yerbadetajo Herb mainly plays the liver provide protection is Coumarether compound Wedelolactone and demethyl wedelolactone, and these two kinds of compositions are at CCl
4, all show stronger liver provide protection (Coumestans asthe main active principles of the liver drugs Elipta alba and wedeliacalendulaced.Wager H in D-Gal and the phalloidin inductive liver injury model; Geyer B; Kisoy; et al.Planta Med; 1986,5:374).Mechanism as for its liver provide protection; have the scholar think by protection Cytolysosome film stability, regulate (the Hepatoprotective effects of Ecliptaalba on subcellular levels in rats.A.K.Saxena that the function of MC drug metabolism enzyme realizes; B.Singh; et al.Journalof Ethnopharmacology; 1993,40:155-156).
In the middle of the document of research Yerbadetajo Herb liver provide protection, most of investigator uses CCl at present
4, the liver injury model that brings out of D-Gal and acetaminophen, the mechanism that they cause liver injury is as follows: CCl
4Generate oxidation activity intermediate product (ROI) by the CYP2E1 metabolism in the liver, thereby cause the destruction and the function damage of biofilm structure, mainly show as peroxidatic reaction of lipid such as liver lobule central area hepatic necrosis, steatosis, reactive hyperplasia; D-Gal can mix formation and the function that normal hexose molecule disturbs membrane structure, thus the inducing hepatocyte necrosis, in addition, it also can make the expression level of liver cell TNF-α mRNA raise, and enhance hepatocyte is to the susceptibility of proinflammatory factor; Acetaminophen P450 metabolism in body can generate active metabolite (NAPQI), and it and the interior macromole generation covalent attachment of liver cell form adducts, thereby bring out the oxidative stress reaction, cause the liver peroxide injury.In the above-described liver injury model, most of by bringing out the oxidative stress reaction, cause acute liver damage.
Autoimmune liver disease is meant that its cause of disease and pathogenesis still imperfectly understand at present owing to one group of disease that hepatic tissue caused of the immune system attack self of body.Clinical common autoimmune liver disease comprises: autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis.
(Autoimmune Hepatitis AIH) is a kind of idiopathic disease that involves liver essence to autoimmune hepatitis.The morphological feature that AIH can not assign a cause for an illness, but typically change into feature with interface hepatitis (interfacehepatitis) and when not having other hepatopathy.Clinically, AIH is characteristics to have autoantibody, the easy trouble of women etc. in fluctuation jaundice, hypergammaglobulinemia, the circulation.This disease is generally replied well glucocorticoid treatment.These feature promptings AIH has unusual autoimmune pathogenesis basis.
(Primary Biliary Cirrhosis is a kind of autoimmunity hepatic diseases PBC) to primary biliary cirrhosis, mainly influences middle-aged women.Mainly show as interlobular bile duct (interlobualr bileduct) chronic nonsuppurative inflammation and granulomatous destruction, and cause carrying out property bile duct to disappear.Thereafter general slow progress of cholestasis and then generation fibrosis, the final liver failure of liver cirrhosis.At present, PBC generally still asymptomatic the patient, find to make when the unusual and/or serum anti-mitochondrial antibody (AMA) of liver biochemistry inspection is positive diagnosis when carrying out routine examination.
(Primary Sclerosing Cholangitis is to turn to the chronic progressive external hepatic diseases of feature in the liver with carrying out property of extrahepatic bile ducts inflammation, obstruction and fiber PSC) to primary sclerosing cholangitis.Bile duct is extensively narrow, at interval with section normal or that expand, thereby has produced the characteristic beading disease in the cholangiography.
Studies show that in a large number the T-lymphocyte that soaks in the liver organization plays a significant role in the pathogenesis of autoimmune liver disease.When a certain composition of liver plasma membrane is given complementary T-cell (TH1 by antigen presenting cell (APC) or by the direct submission of liver cell with HLA II quasi-molecule, TH2) and the restraining effect of suppressor T cell (Ts) weakens or when lacking, the complementary T-cell of activatory will produce the various kinds of cell factor (IL-2, TNF-α, IFN-γ), bring out number of mechanisms and cause hepar damnification.1. irritation cell toxicity T-lymphocyte and HLA I quasi-molecule bonded autoantigen reaction; 2. by IFN-γ activated macrophage; 3. the B-cell changes plasmocyte into, produces autoantibody, or produces antibody-mediated sexual cell destruction by lethal cell and complement.
Viral hepatitis is caused by multiple hepatitis virus, based on one group of common transmittable disease of liver inflammation and downright bad pathology.Serve as main performance with weak, appetite stimulator, hepatalgia, hepatomegaly, dysfunction of liver clinically, jaundice and heating appear in some cases, common symptomless infection.Main by fecal-oral transmission, blood or body fluid communication.Common hepatitis virus has first, second, third, fourth, penta 5 kinds, the transmitted virus (TTV) of transfusing blood in addition in addition.Wherein first type and hepatitis E show as acute hepatitis more, and second, third, fourth type mainly show as chronic hepatitis and can develop into liver cirrhosis and liver cancer.
The pathogeny of viral hepatitis is, hepatitis virus enters blood and liver by routes of transmission such as digestive tube, blood transfusions, thereby activate body fluid and cellular immunization (being mainly the cell-mediated cellular immunization of T), these immune products are further attacked by the liver cell of virus infection, cause a series of pathologic changes such as hepatocellular degeneration, necrosis, hyperplasia and monokaryon or lymphocyte ooze out.In the pathogenic process of chronic viral hepatitis, virus continues to duplicate in liver cell, make liver cell constantly be subjected to immunologic injury, and because the change of the immune-regulating factor generation quality and quantity that the liver cell metabolism forms in the liver due to not normal, thereby cause the immunoloregulation function disorder, the coordination function that reaches between each subgroup of T cell between the T-B lymphocyte is not normal, autoantibody produces and increases, by the cellulotoxic effect of antibody dependence or the cytolysis of antibody-mediated complement dependence, cause the autoimmunization liver damage; Or because the formation of a large amount of antigen-antibody complexes, thereby cause the serious and lasting more infringement of liver or other histoorgans.
In sum, because the liver injury due to the autoimmune liver disease, viral hepatitis is all closely related with the lymphocytic activation of T, still, up to the present, also do not treat the effective ways of autoimmune liver disease and viral hepatitis.
Therefore, a kind of method that can effectively treat autoimmune liver disease and viral hepatitis that provides is provided in this area.
Summary of the invention
The present invention aims to provide a kind of novel substance for the treatment of autoimmune liver disease and viral hepatitis.
In a first aspect of the present invention, Coumarether compound or its pharmacy acceptable salt or the ester of a kind of formula I is provided, perhaps contain the purposes of the extract of the Coumarether compound of formula I or its pharmacy acceptable salt or ester,
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
Described purposes is the medicine that is used to prepare treatment autoimmune liver disease or viral hepatitis.
In another preference, described medicine also is used to suppress the T-lymphopoiesis.
In another preference, described pharmacy acceptable salt or ester are formula I compound and the sour formed salt or the ester that are selected from down group: spirit of salt, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, succsinic acid, oxalic acid, fumaric acid, toxilic acid, oxaloacetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, isethionic acid.
In another preference, described pharmacy acceptable salt is formula I compound and the basic metal or the formed salt of alkaline-earth metal that are selected from down group: sodium, potassium, calcium, magnesium etc.
In another preference, described autoimmune liver disease is selected from down group: autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis; Described viral hepatitis is selected from down group (by the etiology classification): hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E.
In another preference, described formula I compound or described extract extract from feverfew.
In another preference, described feverfew is selected from Eclipta prostrata (Eclipta prostrata Linn), Herbia Wedeliae (Wedelia chinensis), or its combination.
In a second aspect of the present invention, Coumarether compound or its pharmacy acceptable salt or the ester of a kind of formula I is provided, perhaps contain the purposes of the extract of the Coumarether compound of formula I or its pharmacy acceptable salt or ester,
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
Described purposes is to be used to prepare immunomodulator.
In another preference, described conditioning agent also is used to suppress the T-lymphopoiesis.
In another preference, described pharmacy acceptable salt or ester are formula I compound and the sour formed salt or the ester that are selected from down group: spirit of salt, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, succsinic acid, oxalic acid, fumaric acid, toxilic acid, oxaloacetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, isethionic acid.
In another preference, described pharmacy acceptable salt is formula I compound and the basic metal or the formed salt of alkaline-earth metal that are selected from down group: sodium, potassium, calcium, magnesium etc.
In another preference, described formula I compound or described extract extract from feverfew.
In another preference, described feverfew is selected from Eclipta prostrata (Eclipta prostrata Linn), Herbia Wedeliae (Wedelia chinensis), Herba Ecliptae (Eclipta alba), or its combination.
In another preference, described conditioning agent also is used for the treatment of autoimmune liver disease or viral hepatitis.
In another preference, described formula I compound is the Wedelolactone with formula II:
In a third aspect of the present invention, a kind of pharmaceutical composition is provided, it contains
(a) contain formula I compound or its pharmacy acceptable salt or ester, perhaps contain the Coumarether compound of formula I or the extract of its pharmacy acceptable salt or ester as the 0.05-90wt% of main active ingredient
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
(b) be selected from down one or more auxiliary activity compositions of organizing: antiviral; Immunosuppressor; Anti-hepatic fibrosis medicines; Liver-protecting medicine; With
(c) pharmaceutically acceptable carrier.
In another preference, described pharmacy acceptable salt or ester are formula I compound and the sour formed salt or the ester that are selected from down group: spirit of salt, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, succsinic acid, oxalic acid, fumaric acid, toxilic acid, oxaloacetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, isethionic acid.
In another preference, described pharmacy acceptable salt is formula I compound and the basic metal or the formed salt of alkaline-earth metal that are selected from down group: sodium, potassium, calcium, magnesium etc.
In another preference, described formula I compound or described extract extract from feverfew.
In another preference, described feverfew is selected from Eclipta prostrata (Eclipta prostrata Linn), Herbia Wedeliae (Wedelia chinensis), Herba Ecliptae (Eclipta alba), or its combination.
In another preference, described antiviral is selected from down one or more of group: ribavirin, vidarabine phosphate, lamivudine, acyclovir, Famciclovir, Zadaxin; Described immunosuppressor is selected from down one or more of group: prednisone, methyl meticortelone, trypterygine, azathioprine, ciclosporin, tacrolimus (FK506), rapamycin, mycophenolic acid fat, mizoribine; Described anti-hepatic fibrosis medicines is selected from down one or more of group: vitamin A acid, S-adenosylmethionine, colchicine, pentoxifylline; Described liver-protecting medicine is selected from down one or more of group: tiopronin, Sodium Glucuronate, reduced glutathion, Potenlini diamines, aspartic acid ornithine.
In another preference, described composition is selected from injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder inhalation, suppository.
In another preference, described formula I compound is to obtain by the extracting method that may further comprise the steps:
(a) with fruit, leaf or the branch of 95 ± 3% extraction using alcohol feverfews, obtain ethanol extract;
(b) get ethanol extract, in 50-80 ℃ water dissolution of medicinal extract volume, filter and remove impurity, the recovery water with 5-300 times (preferably 10-200 times, more preferably 20-100 doubly);
(c) with the water of ethyl acetate extraction step (b), reclaim the ethyl acetate phase;
(d) ethyl acetate of step (c) is carried out drying mutually, obtain throw out;
(e) on silicagel column, be that sherwood oil/acetone eluent of 5: 1 to 1: 2 carries out the throw out of elution step (c) with gradient, collect sherwood oil: acetone is 1: 1 elution fraction;
(f) elution fraction to step (e) concentrates, and gets enriched material;
(g) on silicagel column, be the enriched material of methylene dichloride/acetone eluent elution step (f) of 5: 1 to 1: 2 with gradient, collect methylene dichloride: acetone is 3: 1 elution fraction;
(h) on silicagel column, be the elution fraction of toluene-acetone-formic acid eluent elution step (g) of 20: 10: 1 to 5: 10: 1 with gradient, collect toluene: acetone: formic acid is 10: 10: 1 elution fraction;
(i) on silicagel column, be the elution fraction of 30: 1 to 1: 1 methylene chloride eluent elution step (h) with gradient, collect methylene dichloride: methyl alcohol is 20: 1 elution fraction;
(j) carry out recrystallization with ethanol, obtain the Coumarether compound precipitation of formula I.
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another.
In view of the above, the invention provides a kind of method that can effectively treat autoimmune liver disease and viral hepatitis.
Embodiment
The contriver is through extensive and deep research, be surprised to find that Coumarether compound or its pharmacy acceptable salt or the ester of a kind of formula I, the plant milk extract that perhaps contains this compound plays a role by suppressing the lymphocytic propagation of T-aspect immunomodulatory, thereby can treat autoimmune liver disease and viral hepatitis effectively
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, C
1-8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another.
Finished the present invention on this basis.
Described alkyl is meant the alkyl of the straight or branched with 1～8 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group etc.The alkyl that preferably has the straight or branched of 1～4 carbon atom.Most preferable.
As used herein, term " composition " comprises the composition of (a) treatment autoimmune liver disease or viral hepatitis, (b) regulates immunity, suppresses the lymphopoietic composition of T-.
Formula I compound can be obtained by extraction in the plant or chemosynthesis, mode semi-synthetic, bio-transformation, for example extracts from feverfew Eclipta prostrata (Eclipta prostrata Linn), Herbia Wedeliae plants such as (Wedelia chinensis).The extract part of this compound in feverfew is branch, leaf or fruit position, the especially leaf site of plant.
Compound of the present invention can use with the form of acceptable salt or ester on pharmacy or the physiology.These salt or ester include, but is not limited to salt or the ester with following acid formation: spirit of salt, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, succsinic acid, oxalic acid, fumaric acid, toxilic acid, oxaloacetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, isethionic acid.Halid salt is suitable equally.Other salt comprise: the salt that forms with basic metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), and the salt (when with this form administration, can change into active part in vivo) that exists with " prodrug " forms of other routines.
The extract that contains formula I compound also can be used for the present invention.A kind of preferred extracting method as mentioned above.Usually, the purity at extract Chinese style I compound should more preferably be 50-98% at 40%-99.9% by weight.
Purposes
Coumarether compound of the present invention or the extract that contains this compound can be used for treating autoimmune liver disease.Representational example comprises (but being not limited to): autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis.
Coumarether compound of the present invention or the extract that contains this compound also can be used for treating viral hepatitis.Representational example comprises (by the etiology classification): hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E.
Coumarether compound of the present invention or the extract that contains this compound also can be used as immunomodulator.
Coumarether compound of the present invention or the extract that contains this compound also can be used for suppressing the lymphocytic propagation of T-.
The effective dose of used activeconstituents can change with the severity of mode of administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 1-100mg.Be applicable to dosage form for oral administration, comprise active compound with the about 0.5-500mg of solid-state or liquid pharmaceutically acceptable carrier blended.Can regulate this treatment plan to reach optimum therapeuticing effect.For example, can be according to the needs of treatment situation, every day, the several times separate administration or reduced dosage in proportion.Usually, becoming the scope of human oral clinical dosage is 1-1000mg/ day, is preferably 10-200mg/ day, and the non-oral dosage of being grown up is 0.1-100mg/ day, preferred 1-100mg/ day.
Using The compounds of this invention or containing the extract for treating autoimmune liver disease of this compound or during viral hepatitis, also can with other treatment agent coupling.For example with one or more auxiliary activity composition couplings that are selected from down group:
Antiviral: ribavirin, vidarabine phosphate, lamivudine, acyclovir, Famciclovir, Zadaxin;
Immunosuppressor: prednisone, methyl meticortelone, trypterygine, azathioprine, ciclosporin, tacrolimus (FK506), rapamycin, mycophenolic acid fat, mizoribine;
Anti-hepatic fibrosis medicines: vitamin A acid, S-adenosylmethionine, colchicine, pentoxifylline;
Liver-protecting medicine: tiopronin, Sodium Glucuronate, reduced glutathion, Potenlini diamines, aspartic acid ornithine.
At the extract that uses The compounds of this invention or contain this compound during as immunomodulator or T-lymphocyte activity inhibitor, also can with other treatment agent coupling.For example (but being not limited to) and be selected from down the group one or more immunosuppressor couplings: prednisone, methyl meticortelone, trypterygine, azathioprine, ciclosporin, tacrolimus (FK506), rapamycin, mycophenolic acid fat, mizoribine.
The present invention also comprises the method for treatment autoimmune liver disease and viral hepatitis, and it comprises the The compounds of this invention to the administration medicine effective quantity.
The present invention also comprises the adjusting immunity, suppresses the lymphopoietic method of T-, and it comprises the The compounds of this invention to the administration medicine effective quantity.
Usually, when The compounds of this invention is used for such use, they can make the pharmaceutical dosage form of different way of administration with one or more pharmaceutically acceptable carriers or mixed with excipients, as injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder inhalation, suppository etc.
But the formulation of oral administration administration is in the above-mentioned formulation: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, secondary calcium phosphate, Microcrystalline Cellulose, sucrose, white bole, micropowder silica gel, talcum powder, low-substituted hydroxypropyl cellulose, sodium starch glycolate, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil).Normally used adjuvant comprises in the process of pharmaceutical compositions: seasonings, tinting material, sanitas (as oxybenzene alkyl butyl ester, Sodium Benzoate, Sorbic Acid) and antioxidant (as vitamin-E, vitamins C, Sodium Pyrosulfite and butylated hydroxytoluene).
The formulation that can be used for injection administration in the above-mentioned formulation comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerine, propylene glycol, polyoxyethylene glycol.In addition, also need add fungistat (as phenylcarbinol, Butylparaben, Thiomersalate), isotonic regulator (as sodium-chlor, glucose), suspending agent (as Xylo-Mucine, methylcellulose gum), solubilizing agent (tween-80, lecithin), antioxidant (as vitamin-E, vitamins C, Sodium Pyrosulfite) and weighting agent (as lactose, N.F,USP MANNITOL).
Can be outside gi tract in the above-mentioned formulation the having of administration: aerosol, powder inhalation, suppository.The carrier example that is fit in the powder inhalation comprises: lactose, dextran, gum arabic, sweet dew, glucose and sodium lauryl sulphate.The solvent that is fit in the aerosol is sterilized water, ethanol, vegetables oil, oleic acid.The propellent that is fit to is Trichloromonofluoromethane, Refrigerant 12, propane, Trimethylmethane, carbonic acid gas, nitrogen.The preparation of suppository can mix medicine and a kind of suitable nonirritant excipient, and vehicle comprises: theobroma oil, polyoxyethylene glycol-4000, polyoxyethylene glycol-6000, ethylparoben, glycerine.
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The preferred oral administration.
Major advantage of the present invention is:
1, Coumarether compound has the effect of obvious treatment autoimmune liver disease and viral hepatitis.
2, Coumarether compound has the effect of the immunity regulated.
3, Coumarether compound has the lymphopoietic effect of the T-of inhibition.
4, described Coumarether compound obtains from natural phant.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all per-cent and umber by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
Extract the compound Wedelolactone in the Herba Ecliptae (Eclipta alba)
(1) immersion and filtration
Herba Ecliptae herb 300kg, immerse fully in 0.75 ton of ethanol (concentration 95%) → soaked overnight (10 hours) → coarse filtration, thereby remove herb residue (reservation) → clean filter (suction filtration) or high speed centrifugation (10000rpm, 10 minutes), thereby remove dust and thin slag → green clear filtrate.
(2) ethanol reclaims
Ethanol is reclaimed in distillation, and temperature is no more than 60 ℃ → each returning and heated up in a steamer 2 hours, the medicinal extract in the reactor is moved to (it is blackish green deeply that medicinal extract is, slightly thick) in the gathering barrel → repetition above-mentioned steps, until reclaiming whole ethanol.
(3) secondary soaks to reach back and heats up in a steamer
Reclaim 0.75 ton of ethanol, soak herb residue → soaked overnight again, coarse filtration, only filter and distill reclaim require the same.Obtain medicinal extract.
(4) ethyl acetate extraction
Get above-mentioned medicinal extract 50-80 ℃ (more preferably 60-70 ℃) and add hot water vibration mixing, the hot water dosage is 50 times of medicinal extract volume, and suction filtration obtains hot water phase liquid.According to water: the ester phase volume ratio is the ethyl acetate that 1: 1 ratio adds extraction usefulness, fully after the mixing concussion, leaves standstill, and treats water/ester phase layering.Shift out ethyl acetate layer, 50 ℃ of vacuum decompressions are distilled to drying, add the small amount of ethanol dissolving, place beaker to spend the night in 4 ℃ of preservations, and precipitation appears in the bottom.Decompress filter obtains precipitation, and 50 ℃ of oven dryings obtain crude product.
(5) product separation is refining
Get crude product 5g, mix sample, carry out silica gel column chromatography (200g in 10g 200～300 order silica gel, the 200-300 order), with sherwood oil-acetone gradient elution, every 100mL collects once, obtain the opposed polarity position respectively, merge (TLC sherwood oil-acetone 1: 1, spot Rf=1/3).After the component that merges concentrated, mix sample again and carry out column chromatography in silica gel, with methylene dichloride-acetone gradient elution, every 50mL collects once, obtains the opposed polarity position respectively, merges (TLC methylene dichloride-acetone 3: 1, spot Rf=1/6).After the component that merges concentrated, mix sample again and carry out column chromatography in silica gel, with toluene-acetone-formic acid gradient elution, every 50mL collects once, obtains the opposed polarity position respectively, merges (TLC toluene-acetone-formic acid 10: 10: 1, spot Rf=1/2).After the component that merges concentrated, mix sample again and carry out column chromatography in silica gel, use the methylene chloride-methanol gradient elution, every 25mL collects once, obtains the opposed polarity position respectively, merging (TLC methylene chloride-methanol 20: 1, spot Rf=1/6).Obtain purity) 90% product, yield about 1%.
(6) standard substance are refining
With purity) 90% sample 30mg is dissolved in 70% methyl alcohol, carries out anti-phase wash-out with Lichroprep RP-18 (40～63 μ) post, detects with TLC, collects 70% sample that elutes, merge to obtain purity) 98% standard substance.Yield about 90%.The proterties of standard substance, molecular formula, fusing point and IR, EIMS,
1HNMR,
13The ownership at CNMR peak is as follows:
Pale powder, molecular formula: C
16H
10O
7, 315 ℃ of mp (decomposition), and UV λ max (MeOH, nm): 211.5 (4.65), 247 (4.40), 304 (4.01) (sh), and 350 (4.48).IR(KBr)cm
-13300，1715，1640，1620，1445，1415，1320，1205，1155，1070。EIMS m/z(％)：314(M
+，100)，313(22)，299([M-CH
3]，28)，285(5)，271([M-CH
3-CO]，8)，243([M-CH
3-CO-CO]，28)，187(17)，69(42)。
1HNMR(δ)：7.23(s)，7.14(s)，6.58(d，J＝2.3Hz)，6.42(d，J＝2.3Hz)，3.90(s)
13CNMR(δ)：158.0(C-1)，101.1(C-2)，159.6(C-3)，95.6(C-4)，99.3(C-5)，161.1(C-6)，95.0(C-7)，155.5(C-8)，155.0(C-9)，104.7(C-10)，145.2(C-11)，144.3(C-12)，99.0(C-13)，114.0(C-14)，148.7(C-15)，55.7(C-16)。
The result shows that the compound of acquisition is the Wedelolactone with formula II:
Extract the Wedelolactone (to call AP-1 in the following text) that obtains by aforesaid method, be used for following each embodiment.
Embodiment 2
Experimental technique:
1. take off vertebra and put to death mouse (male SPF level KM mouse is available from Shanghai Slac Experimental Animal Co., Ltd.), get its spleen under the aseptic condition.Spleen is ground with frosted glass plate, cross film, centrifugal 5 minutes of 300g abandons supernatant.Precipitation adds the 1ml erythrocyte cracked liquid, and mixing left standstill 1 minute, adds PBS solution, and is centrifugal.Behind cell washing 1-2 time, adjust cell concn to 4 * 10 with the RPMI-1640 substratum that contains 10% calf serum
6/ ml;
With cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, place cell culture incubator (37 ℃, 5%CO
2) in cultivate 24h after, the every hole of medication group adds the AP-150 μ l (final concentration is respectively 5 μ M, 10 μ M, 25 μ M, 50 μ M, 100 μ M) of cell culture medium dilution and the ConA (final concentration is 5 μ g/ml) of 50 μ l; The every hole of positive group adds the ConA (final concentration is 5 μ g/ml) of 50 μ l and the cell culture medium of 50 μ l; Negative group adds the cell culture medium of 100 μ l, all establishes 3 multiple holes for every group;
3. after cell being placed incubator to cultivate 40h, every hole adds 25 μ l (0.5 μ Ci/well)
3The H-thymidylic acid;
4. after cultivating 8h, that culture plate is frozen in-20 ℃ of refrigerators.During mensuration with the cell harvesting instrument with cell harvesting to glass fibre membrane, add behind the scintillation solution that (Matrix96 reads on PACKARD) and to mix cell DNA in the Beta calculating instrument
3The H-thymus pyrimidine is examined former times acid, represents the situation of cell proliferation with the CPM value.
Experimental result: see Table 2.
Table 2AP-1 is to the influence of ConA inducer T lymphocyte propagation
| Group | AP-1(μM) | ConA(μg/ml) | CPM | The P value |
| Negative group | - | - | 5143±431 | - |
| Positive group | - | 5 | 246138±2064 △ | - |
| Medicine group 1 | 5 | 5 | 220322±6281 * | 0.0095 |
| Medicine group 2 | 10 | 5 | 174057±1350 * | 0.0018 |
| Medicine group 3 | 25 | 5 | 92641±140 * | 0.0019 |
| Medicine group 4 | 50 | 5 | 33546±483 * | 0.0025 |
| Medicine group 5 | 100 | 5 | 15783±383 * | 0.0022 |
* represent p＜0.01, compare that significant difference is arranged with positive group;
△Expression p＜0.01 is compared with the feminine gender group, and significant difference is arranged.
Lymphopoiesis is the important functional reaction that immunity system is replied antigenic stimulation.With mitogen (ConA) is that the lymphopoiesis model is set up on the basis, can be used for detection of drugs to immune effect.
The result shows that the feminine gender group CPM value that does not add ConA is less, adds the cell proliferation of ConA significant stimulation, and CPM value significantly improves (the positive group: 246138 ± 2064, p＜0.01), for the pharmacodynamic study of AP-1 provides reliable experiment porch.
The result shows that 5 concentration measurement groups all have restraining effect to the lymphocytic propagation of T, and AP-1 has significant inhibitory effect to the lymphocytic propagation of T in concentration during greater than 10 μ M, presents the significant concn dependency.Therefore, to the effect of mitogen ConA inductive T lymphopoiesis, AP-1 presents the restraining effect of concentration dependent.
Embodiment 3
Wedelolactone is to the provide protection of ConA inducing mouse immunological liver injury
1992, Tiegs etc. successfully used concanavalin A (ConA) and have brought out the liver injury of mouse specificity, and it develops into the main experimental model of the hepatic injury of research immunocyte mediation gradually in recent years.
Canavaline (Concanavalin, ConA is a phytohemagglutinin, has the mitogenesis effect, mediate liver injury as mitotic division primary stimuli T lymphocyte expression various kinds of cell factor TNF-α, IFN-γ, IL-2, ConA inducer T lymphocyte dependency liver injury pathology and mankind itself's immunity hepatopathy, acute and chronic hepatitis are similar, and can be alleviated by immunosuppressor.
Give behind the ConA 8 hours, see that promptly plasma A LT, AST, LDH obviously raise, a large amount of T lymphocytic infiltrations in the liver, part portal area lymphocytic infiltration is " oversleeve " sample and changes, and a large amount of liver cell nuclears break, occur apoptotic body and steatosis etc.These prove that all T lymphocyte and this model pathogenesis are closely related.And the hepatic injury due to autoimmune liver disease, viral hepatitis etc. is all closely related with the activation of immunocyte.
Laboratory animal: male SPF level KM mouse, available from (credit number: SCXK (Shanghai) 2003-2003 of Shanghai Slac Experimental Animal Co., Ltd.; Certification of fitness numbering: 0023816), body weight is 18-22g, and SPF level Animal House is raised, and feed and water are freely absorbed in 12h illumination/12h dark.
Experimental technique:
1. modeling method: mouse tail vein injection dosage is the ConA of 20mg/kg;
2. administration situation: the mouse fasting be can't help water after 13 hours, and it is divided into 3 groups (10 every group) respectively at random: (1) normal group, and (2) model group, (1) (2) group mouse gives the distilled water that volume is 0.1ml/10g; (3) positive drug group, mouse give the dexamethasone that dosage is 4.5mg/kg; (4) AP-1 group, mouse gives the AP-1 that dosage is 10mg/kg.Respectively at preceding 5 hours, 1 hour intraperitoneal injection of modeling.
This experiment is by preceding twice administration of ConA modeling prerequisite (being respectively 5 hours and 1 hour), thereby the concentration of medicine in blood is obviously raise, and reaches the treatment significant quantity.
Modeling is plucked eyeball after 8 hours and is got blood, and 4 ℃ left standstill 30 minutes, centrifugal 8 minutes of 3500rpm.Get serum, pass through A with reitman-frankel method
492ALT content in the indirect measurement serum.
Calculate inhibiting rate:
Inhibiting rate=(model group A
492-experimental group A
492)/model group A
492* 100%.
Calculate every cell mean, carry out the one-way variance analysis, and compare between organizing in twos with the SPSS statistical software.
Experimental result: see Table 3.
Table 3 Wedelolactone to the provide protection of ConA inducing mouse immunological liver injury (Mean ± SD, n=10)
| Group | Sex | Quantity (only) | Mean body weight (g) | Absorbance A 492 (X±SD) | Inhibiting rate (%) |
| Normal group | Male | 10 | 19.25 | 0.009±0.001 | - |
| Model group | Male | 10 | 18.70 | 0.108±0.018 △ | - |
| The positive drug group | Male | 10 | 18.61 | 0.014±0.004* | 86.88 |
| The AP-1 group | Male | 10 | 18.58 | 0.024±0.013* | 78.25 |
* represent p＜0.01, compare that significant difference is arranged with model group;
△Expression p＜0.01 is compared with normal group, and significant difference is arranged
The result shows that ALT content (0.108 ± 0.018) is compared with normal group (0.009 ± 0.001) and had significant difference in the model group mice serum, shows the modeling success.
(3), (4) group mice serum in ALT content be starkly lower than model group, difference has significance, inhibiting rate is respectively 78.25% and 86.88%.And compare no significant difference between the group of (3) (4).
The result shows that Wedelolactone has preventative provide protection to the immunity hepatopathy.
Embodiment 4
Wedelolactone is to the therapeutic action of DHBV infected duck
Laboratory animal: commercially available 1 age in days Beijing duck, body weight are the 60-70 gram, freely absorb feed and water.
Experimental technique:
1. modeling method: hatch the Beijing duck within 24 hours, through the positive duck serum of sufficient intravenous injection DHBV-DNA, every 0.2ml got blood after 7 days, separation of serum, and-20 ℃ of preservations are to be checked.
2. administration situation:, be divided into 3 groups at random, 10 every group through 30 of the positive ducks of ELISA method screening DHBsAg.(1) blank group, with the physiologic saline for substitute medicine as blank; (2) positive drug group is pressed 100mg/kg with acycloguanosine (ACV) and is irritated stomach, 2 times/day, 2 weeks of administration; (3) AP-1 group, dosage is 150mg/kg, irritates stomach, 2 times/day, 2 weeks of administration.
Get blood respectively at the 3rd day (P3) after medication the 7th day (T7), the 14th day (T14), the drug withdrawal from duck leg shin vein, separation of serum ,-20 ℃ of preservations are to be checked.
Measure the ALT content in the serum, adopt DHBV-DNA Dot Blot method, with hybridization spot absorbance (A) as sample DHBV-DNA level value.
Calculate every cell mean, carry out the one-way variance analysis, and compare between organizing in twos with the SPSS statistical software.
Experimental result: see Table 4,5.
Table 4 Wedelolactone to the restraining effect of DHBV-DNA (Mean ± SD, n=10)
| Group | Quantity (only) | DHBV-DNA titre before the treatment | Treat back 7 days DHBV-DNA titres | Treat back 14 days DHBV-DNA titres | 3 days DHBV-DNA titres after the drug withdrawal |
| The blank group | 10 | 1.63±0.04 | 1.61±0.03 | 1.59±0.05 | 1.60±0.02 |
| The positive drug group | 10 | 1.58±0.03 | 0.77±0.13* | 0.79±0.14* | 1.56±0.03 |
| The AP-1 group | 10 | 1.65±0.02 | 1.26±0.15* | 1.05±0.05* | 1.11±0.08* |
* represent p＜0.01, compare that significant difference is arranged with the blank group
Table 5 Wedelolactone to the influence of hepatitis B duck Serum ALT (Mean ± SD, n=10)
| Group | Quantity (only) | Before the treatment | Treated back 7 days | Treated back 14 days | After the drug withdrawal 3 days |
| The blank group | 10 | 986.7±135.4 | 976.5±147.1 | 913.5±138.4 | 988.5±92.1 |
| The positive drug group | 10 | 1001.6±131.7 | 598.1±101.6* | 398.4±123.4* | 826.7±131.5 |
| The AP-1 group | 10 | 998.5±142.4 | 813.5±125 | 515.5±108.4* | 546.8±105.6* |
* represent p＜0.01, compare that significant difference is arranged with the blank group
The result of table 4 shows, in the AP-1 group, the titre of DHBV after administration the 7th day and the 14th day is compared with the blank group and to be had significant difference (p＜0.01), and does not have after the drug withdrawal and rebound.ACV has obvious restraining effect to DHBV, but significantly raises again after the drug withdrawal, and compares difference before the administration and does not have significance (p〉0.05).
The result of table 5 shows that ALT content is starkly lower than the blank group in the group mice serum of (2), (3), and difference has significance (p＜0.01); And between the group of (2), (3) relatively, no significant difference.
The result shows that Wedelolactone has therapeutic action to viral hepatitis.
Embodiment 5
The preparation tablet
Utilize routine techniques, mix following component, direct compression then, the pharmaceutical composition of preparation tablet form, its prescription is as follows:
| Composition | Recipe quantity (g/1000 sheet) |
| The AP-1 that embodiment 1 makes | 100 |
| Lactose | 50 |
| Microcrystalline Cellulose | 40 |
| W-Gum | 6 |
| Sodium starch glycolate | 3 |
| Magnesium Stearate | 1 |
| Total amount | 200 |
Embodiment 6
The preparation injection
| Composition | Recipe quantity (g/1000ml) |
| The AP-1 that embodiment 1 makes | 10 |
| Sodium bisulfite | 0.2 |
| Xylo-Mucine | 5 |
| Tween-80 | 1.5 |
| Water for injection | Add to 1000ml |
1. sodium bisulfite is added in the 500ml water for injection, adds Xylo-Mucine, mixing, soaked overnight (24 hours), complete molten after, filter with 210 order nylon cloths;
2. with 1. heating in water bath of solution, add tween-80, mixing;
3. to the water-bath boiling, add Wedelolactone, mixing continues heating 30 minutes, takes out and is cooled to room temperature, G
3Sintered glass funnel filters;
4. add the injection water to 1000ml, mixing, embedding is with 100 ℃ of sterilizations in 30 minutes.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the Coumarether compound of a formula I or its pharmacy acceptable salt or ester perhaps contain the purposes of the extract of the Coumarether compound of formula I or its pharmacy acceptable salt or ester,
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
It is characterized in that, be used to prepare the medicine of treatment autoimmune liver disease or viral hepatitis.
2. purposes as claimed in claim 1 is characterized in that, described medicine also is used to suppress the T-lymphopoiesis.
3. purposes as claimed in claim 1 is characterized in that, described autoimmune liver disease is selected from down group: autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis; Described viral hepatitis is selected from down group: hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E.
4. purposes as claimed in claim 1 is characterized in that, described formula I compound or described extract extract from feverfew.
5. purposes as claimed in claim 4 is characterized in that, described feverfew is selected from Eclipta prostrata (Eclipta prostrata Linn), Herbia Wedeliae (Wedelia chinensis), or its combination.
6. the Coumarether compound of a formula I or its pharmacy acceptable salt or ester perhaps contain the purposes of the extract of the Coumarether compound of formula I or its pharmacy acceptable salt or ester,
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
It is characterized in that, be used to prepare immunomodulator.
7. purposes as claimed in claim 6 is characterized in that, described conditioning agent also is used to suppress the T-lymphopoiesis.
8. as the arbitrary described purposes of claim 6-7, it is characterized in that described conditioning agent also is used for the treatment of autoimmune liver disease or viral hepatitis.
9. as claim 1 or 6 described purposes, it is characterized in that described formula I compound is the Wedelolactone with formula II:
10. a pharmaceutical composition is characterized in that it contains
(a) contain formula I compound or its pharmacy acceptable salt or ester, perhaps contain the Coumarether compound of formula I or the extract of its pharmacy acceptable salt or ester as the 0.05-90wt% of main active ingredient
In the formula,
R
1Represent hydrogen atom, hydroxyl, methoxyl group;
R
2Represent hydrogen atom, hydroxyl, C
1-C
8Alkyl;
R
3And R
4Be selected from hydrogen atom, halogen atom, hydroxyl, methoxyl group independently of one another;
(b) be selected from down one or more auxiliary activity compositions of organizing: antiviral; Immunosuppressor; Anti-hepatic fibrosis medicines; Liver-protecting medicine; With
(c) pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100364582A CN101225087A (en) | 2007-01-15 | 2007-01-15 | Coumarether compound and use of its composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100364582A CN101225087A (en) | 2007-01-15 | 2007-01-15 | Coumarether compound and use of its composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101225087A true CN101225087A (en) | 2008-07-23 |
Family
ID=39857321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100364582A Pending CN101225087A (en) | 2007-01-15 | 2007-01-15 | Coumarether compound and use of its composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101225087A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107669796A (en) * | 2017-11-21 | 2018-02-09 | 菏泽海诺知识产权服务有限公司 | It is a kind of to be used to treat pharmaceutical composition of immunological liver diseases and preparation method thereof |
| CN114409666A (en) * | 2021-12-06 | 2022-04-29 | 江西中医药大学 | A homoisoflavonopolignan compound separated from fructus Hippophae, and its application in preparing medicine for treating non-alcoholic fatty liver disease |
-
2007
- 2007-01-15 CN CNA2007100364582A patent/CN101225087A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107669796A (en) * | 2017-11-21 | 2018-02-09 | 菏泽海诺知识产权服务有限公司 | It is a kind of to be used to treat pharmaceutical composition of immunological liver diseases and preparation method thereof |
| CN114409666A (en) * | 2021-12-06 | 2022-04-29 | 江西中医药大学 | A homoisoflavonopolignan compound separated from fructus Hippophae, and its application in preparing medicine for treating non-alcoholic fatty liver disease |
| CN114409666B (en) * | 2021-12-06 | 2022-12-09 | 江西中医药大学 | A homoisoflavonopolignan compound separated from fructus Hippophae, and its application in preparing medicine for treating non-alcoholic fatty liver disease |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6531505B2 (en) | Immunosuppressive agents | |
| CN1990489B (en) | Use of bohnenkraut ethers compounds and compositions thereof | |
| CN103191174B (en) | Chemical component of eucommia bark used is as the new application of blood vessel protective agent | |
| JP6302102B2 (en) | A compound isolated from MONASCUS PURPUREUS, its preparation and use | |
| Meyer et al. | Novel xanthones from Securidaca longepedunculata with activity against erectile dysfunction | |
| CN101250207B (en) | Canton love-pea vine total flavone c-glycosides effective part, preparation method and use thereof | |
| CN102516344B (en) | Compound with antitumor activity and preparation method and application thereof | |
| CN102379888B (en) | Application of flavone glycoside compounds in preparing medicament for treating and preventing hepatitis | |
| CN103880856B (en) | Bisabolane sesquiterpene derivant and pharmaceutical composition thereof and its application in pharmacy | |
| EP1282613A1 (en) | A pharmaceutical composition containing the extract of saururus chinensis baill useful as and anticancer agent and a process for the preparation thereof | |
| CN101225087A (en) | Coumarether compound and use of its composition | |
| JP2000154151A (en) | Immunosuppressant | |
| CN101480394B (en) | Anti-tumor pharmaceutical composition | |
| CN107383150B (en) | A kind of compound and its preparation method and application with antihepatitis activity | |
| CN100567303C (en) | The purposes of Coumarether compound and composition thereof | |
| US20020173540A1 (en) | TNF-alpha production inhibitor comprising kavalactone as an active ingredient | |
| CN101554382B (en) | New purpose of triterpene substance | |
| CN101492456B (en) | Coumarin ether compounds and new use of composition | |
| CN1321639C (en) | Arthritis therapeutic drug | |
| CN100584345C (en) | Distillage of Ardisia chinensis Benth of possessing function of antivirus, extraction method and application | |
| CN105753681A (en) | Drug composition of citicoline sodium and medical application of drug composition | |
| CN1135979C (en) | Application of sophocarpine in preparation of medicine for curing coxsackievirus B myocarditis and its preparation method | |
| CN102379889B (en) | Application of atemisia gmelinii extract in preparing drugs for preventing liver injuries | |
| CN103845340B (en) | Alisol A 24-acetas prevents and treats the application in arterial disease medicine in preparation | |
| CN101310768B (en) | Medicine composition for treating hepatic disease and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: XIANGBEI WELMAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: SHANGHAI AMBROSIA PHARMACEUTICALS CO., LTD. Effective date: 20100506 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 201203 BUILDING 8, NO.439, CHUNXIAO ROAD, SHANGHAI CITY TO: 410331 ( BIOMEDICAL PARK DISTRICT, DONGYANG VILLAGE, LIUYANG CITY, HUNAN PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20100506 Address after: 410331 Dong Yang Township (Biological Medicine Park), Hunan, Liuyang Province Applicant after: Xiangbei Welman Pharmaceutical Co., Ltd. Address before: 201203 Shanghai Chunxiao Road No. 439 Building No. 8 Applicant before: Shanghai Ambrosia Pharmaceutical Co., Ltd. |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080723 |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080723 |