CN1324009C - Pharmaceutical use of 1-N-methoxy-2-oxo-indole-3-acetamide - Google Patents
Pharmaceutical use of 1-N-methoxy-2-oxo-indole-3-acetamide Download PDFInfo
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- CN1324009C CN1324009C CNB2005100753581A CN200510075358A CN1324009C CN 1324009 C CN1324009 C CN 1324009C CN B2005100753581 A CNB2005100753581 A CN B2005100753581A CN 200510075358 A CN200510075358 A CN 200510075358A CN 1324009 C CN1324009 C CN 1324009C
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Abstract
The present invention discloses a compound which is 1-N-methoxy-2-oxo-indole-3-acetamide. The medicinal preparation of the compound comprises tablets, capsules, pills, granules, dripping pills, oral liquid, suppositories. Enema liquid or injections. The effective dose of the medicinal preparation is from 0.8 mg/kg to 8.0 mg/kg, and the pH range of the preparation is from 2.0 to 5.0. The compound has the exact curative effect on treating endotoxemia and reducing the rate of death caused by multi-viscera nonfunction induced by the endotoxemia.
Description
Technical field
The present invention relates to a kind of pharmaceutical use of compound, particularly the pharmaceutical use of 1-N-methoxyl group-2-oxygen-indole-3-acetamide.Patent application of the present invention is for dividing an application, and the original bill application number is 031020658, and the applying date is on January 30th, 2003, and denomination of invention is a kind of plant milk extract, compound and extracting method thereof and purposes for the treatment of endotoxemia.
Background technology
Intracellular toxin (Endotoxin ET) is lipopolysaccharides (Lipopolysaccharide LPS) composition of leather Lan Shi negative bacillus cell walls, is immunity of mediation human body and the unusual crucial virulence factor of inflammatory reaction.Endotoxemia is to enter circulation of blood by endogenous and exogenous intracellular toxin are excessive, excite the human body immunocyte to discharge the various kinds of cell factor in a large number, destroy human body inflammatory reaction balance, cause microcirculation disturbance and organize major injury, cause extensively and the intensive pathologic reaction, and then high-risk property diseases such as the septic shock that causes, MOFE.In recent years, many studies show that, Sepsis, organ function injury and intestinal endotoxemia that the trauma stress state takes place are closely related.The intestinal mucosa mechanical masking function that occurs under the stress situation is impaired, make than the little intracellular toxin of bacteria particles at first transposition enter blood, cause endotoxemia, activate inflammatory cell, discharge a large amount of inflammatory mediators and cytokine and form Sepsis.Therefore, the generation of endotoxemia not merely is present in the various infectious diseases of inside and outside section, serious wound, burn, shock, major operation and cancer are put, chemotherapy etc. all be the main diseases that produces endotoxemia because of.And endotoxemia be clinical many refractory diseases such as severe complication such as acute lung declines, acute hepatic failure, acute renal failure, acute dic, septic shock and multiple organs dysfunction main diseases because of.Clinical observation confirms that burn patients endotoxemia incidence is 58%, presents significant Sepsis state more, finally can concurrent MODS and death.Occur tangible endotoxemia after the hemorrhagic shock, even Q volume of blood is supplied, pressor agent has been used maximum dose, and shock still can not corrected, and finally is developed to death.The incidence of hepatitis gravis, hepatitis liver cirrhosis, chronic hepatitis, acute hepatitis patient's intestinal endotoxemia (IETM) is respectively 93.3%, 84.3%, 79.0% and 75.0%.In bile duct obstruction and other abdomen operating endotoxemia progress of internal organs illness for renal insufficiency account for 51.4%, develop at last multiple organs failure death up to 28.3%.The multiple organ dysfunction syndrome that endotoxemia is brought out (MODS) is one of modal dead cause of disease of intensive care unit(ICU).Antiendotoxin treatment at the endotoxemia and the MOFE of bringing out is the key subjects and the most active fields of current Chinese scholars research, but does not also have a kind of medicine official listing so far.
Summary of the invention
The object of the invention is to provide the efficient part of Root of Indigowoad and wherein main chemical ingredients; The object of the invention also is to provide the efficient part of Root of Indigowoad and the preparation method of wherein main chemical ingredients; The 3rd purpose of the present invention is to provide the new purposes of the treating endotoxemia of the efficient part of Root of Indigowoad and wherein main chemical ingredients.
From Root of Indigowoad, extract efficient part, can take following any method with treating endotoxemia effect:
Raw medicinal material: the dry root of cruciferae isatis Isatis indigotica Fort..
1, ethanol is made the solvent extraction process of (containing immersion, diacolation, backflow): repeatedly soak or refluxing extraction with 80% ethanol, or use 80% ethanol percolate extraction, united extraction liquid leaves standstill, and gets supernatant liquid filtering, and filtrate recycling ethanol gets the efficient part fluid extract.
2, ion exchange resin extraction process: after a certain amount of Root of Indigowoad soaked, boiling 2 times, each 1.5h-2h, merge water decoction, leave standstill, get the supernatant liquor centrifugation, centrifugate exchanges by storng-acid cation exchange resin, collect effluent liquid, be concentrated into every milliliter of soup and contain about 2 grams of crude drug, add 95% ethanol and make and contain the alcohol amount and reach 80%, staticly settle, get supernatant liquid filtering, filtrate recycling ethanol gets the efficient part fluid extract.
3, macroporous adsorbent resin extraction process: after a certain amount of Root of Indigowoad soaked, boiling 2 times, each 1.5h-2h, merge water decoction, leave standstill, get the supernatant liquor centrifugation, parting liquid passes through macroporous adsorbent resin, respectively with the resin after 10%, 20%, 40%, 50% the ethanol elution absorption, and the collection elutriant, leave standstill, get supernatant liquid filtering, filtrate is reclaimed ethanol respectively, gets the efficient part fluid extract.
4, other organic solvent extraction technology: the medicinal extract thin up of extraction using alcohol is become every milliliter of aqueous solution that contains crude drug 1 gram, use sherwood oil, chloroform extraction respectively successively, sherwood oil, ethyl acetate extraction, sherwood oil, n-butanol extraction.Reclaim the organic solvent in chloroform, ethyl acetate, the butanol extraction liquid respectively, get the efficient part fluid extract.
Four compounds that contain in the efficient part of the present invention are respectively: furfural compounds, lignin compound, Benzazole compounds, organic acid compound.Main effective constituent in the classes of compounds is: the furfural compounds: 5 hydroxymethyl furfural, English name: 5-hydroxymethylfurfural (5-HMF), molecular formula: C
6H
6O
3, molecular weight: 126; Lignin compound: Cyclolariciresinol.English name: Isolariciresinol molecular formula: C
20H
24O
6Molecular weight: 360; Benzazole compounds: 1-N-methoxyl group-2-oxygen-indole-3-acetamide; Organic acid compound: the longer chain fatty acid of anthranilic acid, Whitfield's ointment, phenylformic acid, syringic acid, hydroxyl and two keys etc.Furfural compounds, lignin compound, the Benzazole compounds content 5-60% in efficient part comprises that the content of organic acid compound in efficient part of the longer chain fatty acid of anthranilic acid, Whitfield's ointment, syringic acid, quinazolone acid and hydroxyl and two keys is 5-30%.
The part by weight of the best of breed of effective constituent is in the efficient part: 5 hydroxymethyl furfural 20-50: different tamarack resin alcohol 1-3: 1-N-methoxyl group-2-oxygen-indole-3-acetamide 10-40.
The compounds of this invention clinical application dosage range is respectively: 5 hydroxymethyl furfural is 1.0mg～10.0mg/kg, and different tamarack resin alcohol is 0.1mg～1.0mg/kg, and 1-N-methoxyl group-2-oxygen-indole-3-acetamide is 0.8mg～8.0mg/kg.The pH scope of preparation of the present invention is at 2.0-5.0.
The present invention's compound 1-N-methoxyl group-2-oxygen-indole-3-acetamide that separation obtains from this plant first is the main effective constituent in the efficient part.English name: the 1-N-methoxy-2-oxo-indolyl-3-acetamide structural formula is:
Molecular formula: C
11H
12O
3N
2, molecular weight: 220;
The extracting method of above-mentioned new compound is: the ethyl acetate extract of Root of Indigowoad separates with silica gel column chromatography, uses chloroform successively: methyl alcohol=80: 1 (500ml*18), 40: 1 (500ml*20), 30: 1 (500ml*5), 20: 1 (500ml*32) wash-outs.At chloroform: among stream part 7B of methyl alcohol=40: 1 wash-out two fluorescence spots are arranged, will flow part 7B and continue a column chromatography, further use sherwood oil: chloroform: methyl alcohol=15: 15: 1 wash-outs obtains a white, needle-shaped crystals.
Efficient part of the present invention or its chemical ingredients can be made into pharmaceutically acceptable preparation, for example be prepared into oral Preparation: tablet, capsule, pill, granule, pill, oral liquid, be prepared into the rectal administration preparation: suppository, enema liquid, be prepared into the percutaneous drug delivery preparation: paste, emulsion, liniment, patch, transdermal absorption formulation are prepared into injecting and administering preparations: intramuscular dose, intravenous injection.When the treatment viral infection, active ingredient can or be made compound preparation with suitable virucide administration.This active ingredient can be used as freeze-dried preparation.
Following experimental example is used to further specify the present invention:
Experimental example 1: the present invention confirms that by animal vivo test Root of Indigowoad has the efficient part for the treatment of endotoxemia effect
The test soup: the extract thin up that above each extraction process obtains is made into every milliliter of soup that contains 2 gram crude drugs.
Test intracellular toxin: the O that is provided is provided with Chinese pharmaceutical biological product
111The B4 intestinal bacteria through this prepared in laboratory, purifying intracellular toxin, and are identified the O that is provided with Chinese pharmaceutical biological product
111B
4The escherichia coli endotoxin demarcation of tiring.The mouse dosage range of preparation endotoxemia model is a per kilogram of body weight 15-18 milligram.
Test animal: available from Chinese Academy of Medical Sciences animal reproduction field, Kunming kind, secondary mouse.Weight range: 18-22 gram, male and female half and half.By the body weight random packet, every treated animal is no less than 30.And carry out the t check of each treated animal body weight, and there is not significant difference between each group, take out one group at random and make negative control.
Test method: each treated animal fasting be can't help water 12 hours before the test, the administration group irritates stomach for 0.5 milliliter for different process gained extracting solution by per 20 gram body weight, negative control group is irritated stomach with volume distilled water, after the administration 45 minutes, inject the endotoxin solution of 80% lethal quantity from mouse tail vein, preparation endotoxemia and MOFE model.
Observation index and data processing method: with survival rate and survival time be index, be leading indicator with the survival rate.Observe also and write down in 72 hours, the dead number of elements of every mouse diing time and every group calculates the survival time and the survival rate of every treated animal, and whether there were significant differences between the survival time with t inspection administration group and negative control group, uses X
2Whether there were significant differences between inspection administration group and the negative control group survival rate.Test-results: see Table 1.
The anti-endotoxin effect of the extractive part that table 1 different methods extraction Root of Indigowoad obtains
| Different process extracts component | Survival time (h) | Survival rate (%) | X 2Check (X 2≥3.84) | T checks (P≤0.05) | ||
| Control group | The administration group | Control group | The administration group | |||
| Ethyl acetate fraction extracting n-butyl alcohol position, chloroform extraction position, 80% alcohol extract position cationic ion-exchange resin efflux alcohol extracting position macroporous absorbent resin 10%-50% alcohol wash-out position | 31.15 38.90 31.15 24.57 33.86 25.62 | 67.45 59.33 47.20 45.58 61.56 55.40 | 8/32 12/30 8/32 4/34 9/30 5/30 | 28/32 23/30 18/32 17/34 23/30 20/30 | 22.92 6.86 5.23 9.92 11.32 13.44 | 4.04*10 9 3.33*10 4 9.60*10 4 3.80*10 4 4.04*10-5 3.17*10 -5 |
Conclusion: 6 kinds of extract parts that (1) obtains with above 4 kinds of extraction and separation method all have remarkable treating endotoxemia and reduce the effect of mortality ratio due to its MOFE of bringing out.
(2) in 6 kinds of extract parts, 80% extraction using alcohol part treating endotoxemia and to reduce due to its MOFE of bringing out the effect of mortality ratio the strongest, propyl carbinol, ethyl acetate and chloroform extraction part also have extremely significant treating endotoxemia and reduce the effect of mortality ratio due to its MOFE of bringing out, the 50% following ethanol elution that obtains from macroporous adsorbent resin technology partly has remarkable treating endotoxemia and reduces the effect of mortality ratio due to its MOFE of bringing out, and composition is the middle polarity material in the prompting efficient part.
(3) storng-acid cation exchange resin effluent liquid 80% extraction using alcohol partly has remarkable treating endotoxemia and reduces the effect of mortality ratio due to its MOFE of bringing out, and the part main active ingredient in the prompting efficient part is not by cationic exchange resin adsorption.
(4) after deliberation, mainly contain following four compounds in the efficient part of discovery Root of Indigowoad treating endotoxemia: furfural compounds, lignin compound, Benzazole compounds and organic acid compound.
Experimental example 2: the separation of effective constituent monomeric compound in the efficient part of the present invention: the effective extract part that proves through animal experiment in the above-mentioned table 1, its high performance liquid chromatography has 3 main absorption peaks, and the thin-layer chromatography chromatogram has 3 main spots and curative effect closely related.Because 3 main component content are higher at the ethyl acetate extraction position, are about to the ethyl acetate extraction position and carry out column chromatography for separation.
Material: Haiyang Chemical Plant, Qingdao produces column chromatography silica gel, thin-layer chromatography G plate and GF254 plate.The analytical reagent chloroform of the sharp chemical company of Beijing benefit, methyl alcohol, sherwood oil, ethyl acetate etc.Development system: sherwood oil-chloroform-methanol=4: 4: 1,2: 4: 1, chloroform-methanol=80: 1,40: 1,20: 1.
The Spectrum Analysis of monomeric compound and structural identification: from above component, isolate monomeric compound, determine 25 compounds that have of structure through analytic centre of Military Medical Science Institute mass spectrum, hydrogen spectrum, carbon spectrum analysis and spectrum unscrambling, wherein 22 is known compound, and 3 for separating the compound that obtains first from this plant.
The present invention's compound 1-N-methoxyl group-2-oxygen-indole-3-acetamide that separation obtains from this plant first is the main effective constituent in the efficient part.Its spectral data is as follows: FAB-MS m/z[M+H]
+Be 221.
1HNMR(CDCL3)，δ：2.71(1H，dd，J＝15.9，7.0Hz H-10a)，2.97(1H，dd，J＝15.9，5.7Hz H-10b)，3.85(1H，t，J＝6.4Hz H-3)，4.03(3H，S，OCH
3)，6.09(1H，br.s，-NH)，6.28(1H，br.s，-NH)，6.99(1H，dd，J＝7.8，1.0Hz H-7)，7.09(1H，td，J＝7.8，1.0Hz H-5)，7.32(1H，dd，J＝7.8，1.0Hz H-4)，7.33(1H，td，J＝7.8，1.0Hz H-6)。By
13The CNMR spectrum can infer further that there are two hydroxyls in compound.This compound bismuth potassium iodide test is positive, and is illustrated as alkaloid compound.By mass-spectrometric data and combination
1HNMR,
13The CNMR spectrum infers that the molecular formula of compound 6 is C
11H
12N
2O
3According to the source of students relation, this compound may be Benzazole compounds, and has 2-indolone skeleton.By
1Observed two reactive hydrogens reach among the HNMR
13Existence-C=O-NH2 (acid amides) group is inferred in carbonylation displacement in the CNMR spectrum.
13In the CNMR spectrum δ value be 63.42-OCH3 conforms to this compounds numerical value in the document with 1 N atom is continuous.The molecular formula of inferring this compound in view of the above is: C
11H
12O
3N
2, structural formula is: called after: 1-N-methoxyl group-2-oxygen-indole-3-acetamide.
Experimental example 3: the action intensity of each main component and ratio in the efficient part of the present invention
The preparation of test liquid: acetic acid ethyl ester extract is carried out silica gel column chromatography separate, with chloroform wash-out position and chloroform: methyl alcohol=solvent was reclaimed at the wash-out position in 10: 1, adding water, to be made into concentration be the background solution that contains crude drug amount 2g/ml, 5 hydroxymethyl furfural, different fallen leaves pine tree alcohol ester, 1-N-methoxyl group-2-oxygen-indole-3-acetamide that chloroform-methanol different ratios wash-out is obtained than adding in the background liquid, screen best proportioning by Different Weight.For guaranteeing the stability of effective constituent, the background solution of No. 3 efficient parts is transferred pH=2.5 with 5% hydrochloric acid, and the background solution of No. 6 efficient parts is transferred pH=4.5 with 5% sodium hydroxide, and it is the same that experimental animal, medication and result add up.Test-results sees Table 2.
Each main component ratio of table 2 and corresponding results of pharmacodynamic test
| The medicine-feeding part numbering | Each position proportion (weight ratio) | The animal experiment data | ||||
| 5-HMF | Different fallen leaves pine tree alcohol ester | 1-N-methoxyl group-2-oxygen-indole-3-acetamide | Soup pH value | X 2Check (X 2≥3.84) | T checks (P≤0.05) | |
| Medicine-feeding part 1 medicine-feeding part 2 medicine-feeding parts 3 medicine-feeding parts 4 medicine-feeding parts 5 medicine-feeding parts 6 background solution 7 | 17.00 17.00 51.00 0.00 0.00 0.00 0.00 | 1.00 1.00 0.00 1.00 1.50 0.00 0.00 | 15.0 0.00 0.00 7.5 0.00 30.0 0.00 | 4.00 2.80 2.50 3.80 3.50 4.50 3.50 | 20.43 13.08 4.19 4.22 3.95 4.19 0.00 | 5.16*10 9 7.04*10 5 0.05 0.01 0.00 0.05 0.00 |
Conclusion:
(1) in the 5 hydroxymethyl furfural in the efficient part, different tamarack resin alcohol, 1-N-methoxyl group-3 main component Individual existences of the 2-oxygen-indole-3-acetamide background solution, all can reduce the mouse death rate due to the MOFE that endotoxemia brings out significantly.
(2) with under the dosage condition, the action intensity of various combinations is: 5 hydroxymethyl furfural+different tamarack resin alcohol+1-N-methoxyl group-2-oxygen-indole-3-acetamide＞5 hydroxymethyl furfural+different tamarack resin alcohol＞different tamarack resin alcohol+1-N-methoxyl group-2-oxygen-indole-3-acetamide.
(3) part by weight of the best of breed of effective constituent is in the efficient part: 5 hydroxymethyl furfural 20-50: different tamarack resin alcohol 1-3: 1-N-methoxyl group-2-oxygen-indole-3-acetamide 10-40.
(4) action intensity of each effective constituent, the combination of effective constituent different ratios is relevant with concentration separately in the efficient part, strengthens with concentration increase effect.
(5) the main effective constituent in the efficient part is that 5 hydroxymethyl furfural, different tamarack resin alcohol, 1-N-methoxyl group-2-oxygen-indole-3-acetamide, organic acid can be used as the quality control index that the present invention treats the efficient part of endotoxemia.
(6) 5 hydroxymethyl furfural to the treatment concentration range of the mouse endotoxemia and the MOFE of bringing out at per kilogram of body weight 10mg～100mg/kg, at per kilogram of body weight 1mg～10.0mg/kg, the treatment concentration range of 1-N-methoxyl group-2-oxygen-indole-3-acetamide is at per kilogram of body weight 8mg～80.0mg/kg to the treatment concentration range of mouse for different tamarack resin alcohol.
The principal indication of efficient part of the present invention: efficient part of the present invention can reduce the mortality ratio of the Sepsis of being brought out by endotoxemia, septic shock, MOFE effectively.Be applicable to serious wound (burn, fight) wound, infection, major operation, severe hemorrhagic shock, put the endotoxemia that produces under the stress situations such as (change) treatment, organ transplantation, concurrent endotoxemias such as hepatitis gravis, liver cirrhosis, gastrointestinal tract disease, malnutrition, biliary tract/intestinal obstruction, Sepsis, septic shock, multiple organs dysfunction even the depletion brought out by endotoxemia.This efficient part has the clearing heat and detoxicating of theory of traditional Chinese medical science, activate blood circulation and disperse blood clots, the recuperating deplered YANG and rescuing the patient from collapse effect, be applicable to the warm disease witness of the evil straight middle defensive-qi-nutrient-blood of heat poison: as the excessive noxious heat of septicemia, the heat poison of acute pneumonia becomes silted up to wet to stop up and stagnates in lung the scorchingly hot string of attacking of acute hepatic failure, damp-heat gluing each other, the heresy of the heat poison of acute dic is gone into ying blood, and disease etc. is taken off in fainting of severe hemorrhagic shock.
This efficient part can treat or prevent any and the LPS diseases associated effectively, and described disease includes, but are not limited to endotoxemia (or Sepsis syndromes), also suppresses the generation of the virus of LPS stimulation.The effect of duplicating of these viruses is the control that directly or indirectly is subjected to the NF-KB regulatory region.These viruses comprise cytomegalovirus, simplexvirus, but be not limited to this, in addition, because the activation of influenza virus is subjected to that the effect of LPS strengthens and the increase of TNF-α burst size is relevant with the comprehensive condition of influenza virus A and bacterial infection, the present invention also may play restraining effect to the activation of influenza virus.
Embodiment 1:
5 hydroxymethyl furfural 120 gram adds vehicle system particle 300 grams routinely, fills and makes 1000 of 0.3 gram/capsules, and modulator ph value is 2-5, day 3 times, each 1 oral.
Embodiment 2:
Different tamarack resin alcohol 2 grams add PEG-6000 48 grams, and modulator ph value is 2-5, and heating and melting drips and makes 1000 of 50 milligrams of/dripping pills, day 3 times, each 5, sublingual administration.
Embodiment 3:
1-N-methoxyl group-2-oxygen-indole-3-acetamide 120g adds vehicle routinely, modulator, system particle 300 gram is pressed into 1000 in the tablet of 0.3 gram/sheet, day 3 times, each 1 oral.
Embodiment 4:
5 hydroxymethyl furfural: different tamarack resin alcohol: 1-N-methoxyl group-2-oxygen-indole-3-acetamide=15.0: 1.0: 15.0, totally 100.0 grams add vehicle routinely, modulator, system particle 300 grams are filled and are made 1000 of 0.3 gram/capsules.Days 3 times, each 1 oral.
Claims (7)
1, a kind of compound is characterized in that this compound is 1-N-methoxyl group-2-oxygen-indole-3-acetamide.
2, a kind of pharmaceutical preparation that contains the described compound of claim 1 is characterized in that this compound medicine preparation is tablet, capsule, pill, granule, pill, oral liquid, suppository, enema liquid or injection.
3, compound as claimed in claim 1 is in the serious endotoxemia that produces under burning, war wound, infection, major operation, severe hemorrhagic shock, radiotherapy, chemotherapy, the organ transplantation stress situation of creating of preparation treatment; Application in endotoxemia that hepatitis gravis, liver cirrhosis, gastrointestinal tract disease, malnutrition, biliary tract intestinal obstruction are concurrent or the Sepsis of bringing out, septic shock, multiple organs dysfunction or the depleted medicine by endotoxemia.
4, the pharmaceutical preparation of compound as claimed in claim 2 is in the serious endotoxemia that produces under burning, war wound, infection, major operation, severe hemorrhagic shock, radiotherapy, chemotherapy, the organ transplantation stress situation of creating of preparation treatment; Application in endotoxemia that hepatitis gravis, liver cirrhosis, gastrointestinal tract disease, malnutrition, biliary tract intestinal obstruction are concurrent or the Sepsis of bringing out, septic shock, multiple organs dysfunction or the depleted medicine by endotoxemia.
5, compound as claimed in claim 1 takes off application in the medicine of the disease that disease and cytomegalovirus, simplexvirus influenza virus cause fainting of preparation treatment septicemia, acute pneumonia, acute hepatic failure, acute dic, severe hemorrhagic shock.
6, the pharmaceutical preparation of compound as claimed in claim 2 takes off application in the medicine of the disease that disease and cytomegalovirus, simplexvirus, influenza virus cause fainting of preparation treatment septicemia, acute pneumonia, acute hepatic failure, acute dic, severe hemorrhagic shock.
7, the preparation method of compound as claimed in claim 1 is characterized in that this method is:
The ethyl acetate extract of Root of Indigowoad separates with silica gel column chromatography, uses chloroform successively: methyl alcohol=80: 1,40: 1,30: 1,20: 1 wash-outs; At chloroform: among stream part 7B of methyl alcohol=40: 1 wash-out two fluorescence spots are arranged, will flow a part 7B column chromatography, use sherwood oil: chloroform: methyl alcohol=15: 15: 1 wash-outs, acquisition white, needle-shaped crystals.
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| CN 03102065 CN1251698C (en) | 2003-01-30 | 2003-01-30 | Plant extract and compound for treating endotoxin blood disease, and its extraction method and application |
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| CN 03102065 Division CN1251698C (en) | 2003-01-30 | 2003-01-30 | Plant extract and compound for treating endotoxin blood disease, and its extraction method and application |
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| CNB2005100753581A Expired - Fee Related CN1324009C (en) | 2003-01-30 | 2003-01-30 | Pharmaceutical use of 1-N-methoxy-2-oxo-indole-3-acetamide |
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| CN101385750B (en) * | 2007-09-14 | 2011-09-28 | 四川省泰信动物药业有限公司 | Preparation method of effective ingredient of isatis root |
| CN101234134B (en) * | 2008-02-27 | 2011-01-05 | 广州白云山和记黄埔中药有限公司 | Application of compound isatis root preparation in preparing medicaments for preventing and controlling endotoxaemia |
| CN101933966B (en) * | 2010-08-31 | 2011-12-21 | 南京中医药大学 | Active site composition of isatis roots, as well as preparation method and application thereof |
| CN102614206A (en) * | 2011-01-31 | 2012-08-01 | 澳门科技大学 | Application of 7S,8R,8'R-(+)-lariciresinol-4,4'-bi-O-beta-D-glucopyranoside in preparing medicines |
| CN106565468A (en) * | 2016-11-15 | 2017-04-19 | 河南中医药大学 | Syringic acid extracted from mulberry barks, preparation method for syringic acid and application of syringic acid |
| CN109438221B (en) * | 2018-11-21 | 2021-09-03 | 集美大学 | Method for preparing syringic acid from spirulina |
| CN111450135A (en) * | 2020-05-18 | 2020-07-28 | 山西省芮城县红宝兽药有限责任公司 | High-purity radix isatidis and preparation method of injection thereof |
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| WO1998002419A1 (en) * | 1996-07-12 | 1998-01-22 | Chugai Seiyaku Kabushiki Kaisha | Cancer cell proliferation inhibitors |
| US5952511A (en) * | 1993-02-17 | 1999-09-14 | Chugai Seiyaku Kabushiki Kaisha | Indolin-2-one derivatives |
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2003
- 2003-01-30 CN CN 03102065 patent/CN1251698C/en not_active Expired - Fee Related
- 2003-01-30 CN CNB2005100753581A patent/CN1324009C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5952511A (en) * | 1993-02-17 | 1999-09-14 | Chugai Seiyaku Kabushiki Kaisha | Indolin-2-one derivatives |
| WO1998002419A1 (en) * | 1996-07-12 | 1998-01-22 | Chugai Seiyaku Kabushiki Kaisha | Cancer cell proliferation inhibitors |
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| Title |
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| 四倍体板蓝根中的两个新生物碱 李彬等，药学学报，第35卷第7期 2000 * |
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| CN1251698C (en) | 2006-04-19 |
| CN1704401A (en) | 2005-12-07 |
| CN1520837A (en) | 2004-08-18 |
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