CN1046700C - Reduction of the sennoside mixture to the corresponding anthrone compounds - Google Patents
Reduction of the sennoside mixture to the corresponding anthrone compounds Download PDFInfo
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- CN1046700C CN1046700C CN 92115357 CN92115357A CN1046700C CN 1046700 C CN1046700 C CN 1046700C CN 92115357 CN92115357 CN 92115357 CN 92115357 A CN92115357 A CN 92115357A CN 1046700 C CN1046700 C CN 1046700C
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Abstract
The present provides a method for obtaining diacetyl rhein. Liquid-liquid distribution is carried out to diacetyl rhein containing the components of alose and emodin between polarity organic solvent which is partially mixed with water and water phases with the pH of 6.5 to 7.5, diacetyl rhein is recovered, and recrystallization is carried out freely. The present invention also relates to diacetyl rhein obtained by the method and a medical composition containing the compound.
Description
The present invention relates to a kind of method that contains less than the diacetyl rhein residual volume of not expecting the rhabarberone derivative, medicinal purity of 20ppm that obtains to amount to, according to this method diacetyl rheum officinale acyl that obtains and the pharmaceutical composition that contains this compound.
Chemical formula
Diacetyl rhein be a kind of medicinal activity compound, it has curing arthritis, anti-inflammatory, brings down a fever and analgesic activity.Therefore, diacetyl rhein can be used for the treatment of arthritis disease (referring to, for example, DE-A-27 11 493 and US-A-4,244,968).
Diacetyl rhein can pass through; for example the acetylize of Barbaloin A and the acetylize Barbaloin A excessively that obtains and the oxidation of chromium trioxide prepare, and in addition, diacetyl rhein can be by the rhubarb yellow that is easy to get; for example, the rhubarb yellow that obtains from the sennae medicine prepares through acetylize.
The diacetyl rhein that makes according to last these methods contains the association rhabarberone derivative of not expecting, this material be obtain by incomplete oxidation with chromium trioxide or in sennae medicine extraction process, extract jointly.These association materials exist with relatively little amount and only separate with known purifying technique and have very big difficulty.In addition, have the chromium resistates to exist in the above under the situation of first method of mentioning, it must be removed with appropriate means.
Therefore, it is simple that one of purpose of the present invention provides a kind of process, the method of the acquisition diacetyl rhein that productive rate is high, the diacetyl rhein that wherein makes are to contain the diacetyl rhein with medicinal purity of not expecting rhabarberone derivative residual volume less than 20ppm.
Therefore, according to the present invention, it provides a kind of method for preparing diacetyl rhein, wherein containing aloe---emodin derivates is (for example, liquid distributes aloe---Schuttgelb and/or its derivative) diacetyl rhein carry out liquid containing of 6.5-7.5 between the water in a kind of only part and miscible polar organic solvent and a kind of PH of water---, obtains diacetyl rhein and and then at random carries out recrystallization thereby reclaim.
Containing aloe---the diacetyl rhein of Schuttgelb can be used for the method according to this invention, and the important source of diacetyl rhein is the sennoside that contains the sennae medicine, and the rhubarb yellow-9-anthrone-8-glucoside that can obtain from sennoside.
Therefore, the preferred embodiment of the invention is that a kind of preparation is substantially free of aloe---the method for the diacetyl rhein of emodin derivates, wherein
A) will contain aloe---the rhubarb yellow-9-anthrone-8-glucoside of Schuttgelb compound is oxidized to corresponding anthraquinone compounds,
B) glucose residue on anthraquinone compounds 8-position is split off in acid medium,
C) will obtain 1, the acetylize of 8-dihydroxy-anthracene naphtoquinone compounds and
D) thus products therefrom at a kind of only part and the miscible polar organic solvent of water with have between the water that pH value is 6.5-7.5 and carry out liquid---liquid distributes and reclaims diacetyl rhein and and then at random carry out recrystallization.
Another embodiment preferred of the present invention is that a kind of preparation is substantially free of aloe---the method for the diacetyl rhein of emodin derivates, wherein
A) the sennoside mixture transforms into corresponding anthrone compound through reduction,
B) oxygenated anthrone that obtains is oxidized to corresponding anthraquinone compounds,
C) glucose residue on anthraquinone compounds 8-position is split off in acid medium,
D) will obtain 1, the acetylize of 8-dihydroxy-anthracene naphtoquinone compounds and
E) thus products therefrom carries out liquid between the water that a kind of only part and the miscible polar organic solvent of water and PH are 6.5-7.5---liquid distributes and reclaims diacetyl rhein, and and then at random carries out recrystallization.
To each step of the inventive method be described in detail below
The sennoside mixture changes into the reduction reaction of corresponding anthrone compound
Sennoside mixture as initiator for example, can obtain from the sennae medicine.The sennae medicine is by the sennae plant, for example indian senna (the narrow leaf of Cassia tora) and alexandria senna (the sharp sharp leaf of Cassia tora), cured leaf and fruit form.Described sennae medicine contains rhubarb yellow and aloe---the dianthrone glucoside of Schuttgelb.It the most important thing is sennoside A, B, A1, C, D and D1.Sennoside is corresponding to general formula:
At sennoside A, R represents COOH in the situation of B and A1, and at sennoside C, in the situation of D and D1, R represents CH
2OH.Sennoside A, B and A1 and rush down leaf glycosides C, D and D1 be steric isomer and its 10 with 10 ' carbon atom on configuration different mutually.
For example from the sennae medicine, obtain sennoside, in DE-A-3200131, be described, at this as a reference to improve explanation to invention.According to the described method of the document, the sennae medicine at first extracts with aqueous methanol.After removing methyl alcohol fully, contain an alkali metal salt in the concentrated solution of remnants, particularly the sennoside of potassium salt form existence.This enriched material is with alcohol or ketone, and for example fourth-2-alcohol or fourth-2-ketone (they can partly be dissolved in (raffinate) in the water) passes through that liquid---liquid extracts purifies.Make its pH value be about 1.5-2.0 and the sennoside crystallization is separated out this raffinate acidifying, the thick sennoside mixture that obtains can be as the initiator of the inventive method.Also can make this thick sennoside mixture recrystallization if desired.
On the other hand, with the alcohol that only is partially soluble in water, particularly fourth-2-alcohol blended enriched material can be as the initiator of the inventive method.
In the process of extraction sennae medicine, this medicine is preferably 1: 4 to 1: 15 to the ratio of extraction liquid, is preferably 1: 4 to 1: 10.
This extraction is preferably under the existence of buffer reagent to be carried out, and buffer reagent for example can be trisodium citrate, glycine, sodium bicarbonate or sucrose.
The method according to this invention, these initiators are reduced to make rhubarb yellow-9-anthrone-8-glucoside (R=COOH) and aloe---Schuttgelb-9-anthrone-8-glucoside (R=CH
2OH), its general formula is
Wherein R is COOH or CH
2OH.
Reductive agent with suitable reducing power comprises tin protoxide, sulfurous gas, alkali metal borohydride and preferably basic metal hyposulfite, particularly V-Brite B.Reductive agent is with a large amount of excessive uses.Generally, hyposulfite and preferably V-Brite B use with 1-4 times of weight (with respect to the content of sennoside in the initiator).
For carrying out this reduction reaction, this initiator can aqueous solution or the form of suspension exist, reductive agent adds wherein with solid or form soluble in water.Preferably in two-phase mixture, finish, promptly by to wherein be added to many parts ground and water miscible polar organic solvent, especially fourth-2 '-alcohol finishes.
This reductive action preferably is preferably in 50-55 ℃ and be to carry out under the condition of 7-9 at pH value at 40-60 ℃.Reduction reaction is preferably divided preferably to divide several times and is carried out for 2-10 time.
9-anthrone-8-the glucoside that forms is by adding acid, and for example to make its PH be that 4-4.5 is precipitated out to sulfuric acid.Its temperature should be advisable to be no more than 40 ℃.Under the situation of precipitation anthrone glucoside and under its segregation situation, for example overanxious, preferably under nitrogen atmosphere, carry out so that avoid the uncontrolled oxidation of these compounds.
The anthrone compound changes into the oxidizing reaction of anthraquinone compounds
Now the anthrone compound oxidation that obtains is become corresponding anthraquinone compounds, its general formula is:
Wherein R is COOH or CH
2OH.The oxygenant that is suitable for comprises, oxygen for example, and superoxide, as hydrogen peroxide, the manganese of high oxidation state, chromium and iron cpd.Preferably use molysite, be preferably ferric sulfate.This process is preferably in the temperature of rising but carries out being lower than under 60 ℃ of temperature.Thereby avoid that do not expect and formation uncertain oxidation products.Behind complete oxidation, anthraquinone-8-glucoside is emanated with ordinary method.
The division of glucosyl residue
Glucose residue on anthraquinone compounds 8-position divides in acid solution.Preferably under about 85-95 ℃ temperature, carry out.The product that obtains is emanated with ordinary method.
Behind acidic hydrolysis, be known technology (referring to for example DE-A-2711493) by sennoside directly being changed into rhubarb yellow with ferric chloride reaction.But the productive rate that obtains thus only is 10%, and in addition, the rhubarb yellow of formation also is difficult to separate.
In the method for the invention, the reductive cleavage of sennoside, the anthrone compound oxidation of formation become the division of the glucose residue on corresponding anthraquinone compounds and the anthraquinone compounds 8-position, and wherein each process all is to finish in separation steps.Surprisingly in this method, the productive rate of rhubarb yellow is 89%.In addition, thus oxidation can carry out having avoided that do not expect and formation undetermined oxidation products under moderate moisture.When carrying out this reaction, used molysite almost can be reclaimed quantitatively in addition, and behind reoxidation, can use again.Because it is more water-soluble that the anthrone glucoside has been compared with above-mentioned aglycone, oxidation step and hydrolysing step are separated and can allow.In envrionment temperature or be lower than under 60 ℃ of temperature and carry out the demulcent oxidizing reaction, avoided inevitably not determining the formation of by product thus.
1, the acetylize of 8-dihydroxy-anthracene naphtoquinone compounds
The acetylize of 1, the 8 dihydroxy-anthracene naphtoquinone compounds that obtains can be carried out with ordinary method.For example, can in the presence of sodium acetate, finish acetylize with acetic anhydride, promptly at Arch.Pharm., the method described in 241,607/1903.Yet known other method of the also available specialty of this acetylize is carried out, for example by carrying out with excess acetyl chloride, or the like.
Liquid---liquid distributes
Obtain the liquid of product---it is to be that the aqueous phase that contains of 6.5-7.5 carries out at the organic liquor of polarity and pH value that liquid distributes, and said polar solvent only part is miscible with water at the most.Suitable polar organic solvent comprises C
4-C
5-alkanol and C
1-C
3Dialkyl ketone is fourth-1-alcohol for example, fourth-2-alcohol, and isopropylcarbinol and fourth-2-ketone, last is preferred.
Than heavy phase and light volume ratio mutually generally in 1: 2 to 2: 1 scope.Be the solution of diacetyl anthraquinone compounds in polar organic solvent mutually gently.As being that PH is the water of 6.5-7.5 than heavy phase, its pH value is regulated with the most handy acetic ester buffer reagent of buffer reagent preferably.
Liquid---the liquid extraction liquid preferably carries out in adverse current, and diacetyl rhein is introduced in the organic phase with the concentration of about 0.01M thus,
After distributing, required diacetyl rhein is present in than in the heavy phase.Make its precipitation by its pH value is acidified to about 5.2, reclaim with usual method then, diacetyl rhein as an alkali metal salt and preferably as the form recrystallization of sylvite, is changed into insoluble free acid with this salt then.In addition, also direct recrystallization from ethyl lactate of diacetyl rhein.
The diacetyl rhein that obtains in this way is substantially free of aloe---Schuttgelb and its derivative.The 50ppm but the actual content of these impurity is still had an appointment (determining) by the analytical procedure described in the embodiment below.The content of these impurity can further reduce during recrystallization in the following method at the diacetyl rhein that will obtain.Diacetyl rhein can be by changing into an alkali metal salt with suitable alkaline purification, and suitable alkali can be for example alkali metal acetate, preferably potassium acetate.Preferably use the alkali and the moisture C of equivalent
1-C
3Alcohol, for example 80-90% ethanol is as reaction medium.An alkali metal salt of diacetyl rhein can crystallization under cold condition, adds then and contains C
1-C
3Alcohol makes its PH be settled out for about 3 by adding acid again.The diacetyl rhein that is settled out uses the usual method segregation and processes.As a kind of variation measure, can directly from ethyl lactate, carry out recrystallization.
The product that obtains like this contains the above-mentioned impurity that is less than 20ppm.On the other hand, this product can the needle-like crystal form exist, and this crystalline form is particularly useful for herb formulation.
This product can be used the usual method drying.Be preferably the first step in vacuum and relatively low temperature is dry as not being higher than under 40 ℃ of temperature, drop to about 3% or still less up to the water-content of product.Then raise the temperature to 70-110 ℃ and carry out drying.
The pure basically diacetyl rhein that the present invention also relates to obtain, and the pharmaceutical composition that contains this compound according to the present invention.In the used field, the dosage that should use and the suitable form of medicine all are known and are described in for example US-A-4,244,968, US-A-4,346,103, US-A-4,950,687 and DE-A-2711493, and at Drugs Exptl.Clin.Res., 6 (1), among the 53-64/1980.
The following examples are further specifying the object of the invention.Embodiment 1 obtains the sennoside mixture as initiator
In each case, 40kg sennae medicine (sennoside content about 1.5%) is joined in 2 placed in-line percolators, each volume is 250 liters and covers with stephanoporate steel plate.70% methyl alcohol that uses as extraction solvent feeds in the medicine in first percolator.The solution that forms in first percolator is passed in second percolator that medicine is housed, and makes solvent freely by first percolator thus.
To use and amount to 160 liters solvent in order to extract 40% sennae medicine.At 70% methyl alcohol of 160 liters of volumes by these two percolators and after having collected the filtrate of respective amount, with the diafiltration organ pipe of sky and back one diafiltration container coupling and 60 liter of 70% methyl alcohol that will be left by these two percolators.After this, make the top of the remaining solvent that comes out from first percolator by second percolator, it is 120 liters that this back one transudate is recovered up to its amount.After first percolator was found time, the sennae medicine of the 40kg that packs into again also was pumped into the back transudate on this medicine, and at this, filtrate is enough to cover the medicine in this percolator after 120 liters.
Secondly, the temperature regulation with solution arrives+30 ℃.
This percolator is connected on the stripped in advance percolator, and extraction is finished with aforesaid method.
To every 40kg medicine, can collect 150 liters of transudates, methyl alcohol wherein can be removed in the vacuum rotary evaporator of packing tower is housed.Thereby can obtain 30 liters of bottom products (enriched material), it can use 40 liters with the extraction of water saturated fourth-2-alcohol in 10 grades of mixer-settler equipment.Obtain moisture raffinate and the pure extraction liquid of fourth-2-of about 30-32 liter that about 38-40 rises like this.
When stirring moisture raffinate being reached more than 20 hours with 93% sulfuric acid acidation, is to need 1.6% of acidifying liquid volume at the volume of this used acid.Its souring soln has the pH value of 1.5-2.0.Further stirred 6 days, make static the spending the night of precipitation, filter, wash with water till the water colorless of washing, with dry in methanol wash and the airflow at room temperature.The coarse raw materials of every 40kg obtains the thick sennoside of 760-790g (dry-matter), and wherein sennoside content is 90-94%.Therefore, the sennoside amount of gained accounts for 70% of the sennoside amount that is present in the coarse raw materials.The step a) sennoside is reduced into rhubarb yellow-9-anthrone-8-glucoside
The V-Brite B of 9.0kg is dissolved in 100 liters the softening water, when stirring, with the 3.0kg sennoside A that has an appointment that contains that obtains, the thick sennoside of A1 and B is metered in the above-mentioned solution.Under 50-58 ℃, this homogeneous phase solution was stirred 2 hours, be cooled to 50-55 ℃ then.(weight) sulfuric acid of using 96-98% then is to precipitate under 4.2 the condition at pH value.With the suspension restir that obtains 1.5 hours, its highest temperature was 25 ℃, filters under nitrogen atmosphere then.Resistates washs with 50 liters of softening waters, and it is 2 that this softening water is transferred to PH with sulfuric acid, according to covering (it prepares referring to step 3b) with 10 liters of ferrum sulfuricum oxydatum solutums.Step b) is oxidized to rhubarb yellow-8-glucoside
To be suspended in the hydrate (22%Fe of 184 liters of softening waters and 75.7kg ferric sulfate from the product that the last step obtains
3+) solution in.This suspension is heated to 55-62 ℃ also with quick flow dispersion agent oxidation 14 hours.When oxidation is finished, filter out rhubarb yellow-8-glucose, and wash with 50 liters of softening waters (regulating pH value with sulfuric acid is 2).Step c) is hydrolyzed into rhubarb yellow
To be suspended in 200kg20% (weight) sulfuric acid and from the wet filtration residual solution that step b) obtains and stir 8 hours down at 88-92 ℃.The rhubarb yellow that forms is filtered out, in order to store, can be under 40 ℃ of 1mbar vacuum tightnesss dry 48 hours, or also can under wet state, carry out the acetylize of step d) immediately.
The overall yield of step a)-c) is 89%, with respect to sennoside A, A1 and B used in step a).The step d) acetylize obtains diacetyl rhein
The 6.5kg rhubarb yellow that will obtain from step c) was suspended in 100 liters the acetic anhydride 10 minutes, mixed with the 2kg potassium acetate, was heated to 95 ℃ simultaneously stirring, and mixed being incorporated in 90-95 ℃ and stirring 30 minutes down with the gac of 0.65kg.Gac is filtered out from hot solution, under 90 ℃, the sulfuric acid of filtrate with 2.1kg96-98% (weight) is mixed.When stirring, with as far as possible fast speed make it be cooled to the 20 ℃ also suspension of filter result gained thereafter.Residual solution does not exist to there being vitriol with the softening water washing.Productive rate is 83%.Step e) is removed free and acetylizad rhabarberone
Aloe---the Schuttgelb part is removed by counter-current extraction in having the pulsed extraction column of 15 blocks of theoretical trays at least.Is 1: 1 than heavy phase with light volume ratio mutually.As than heavy phase, used 0.1 mole of aqueous acetic acid potassium solution with fourth-2-alcohol is saturated.Form by water saturated fourth-2-ketone mutually in, make 0.01 mole of the diacetyl rhein dissolving that will purify.By using 10% (weight) sulfuric acid under PH5.2, diacetyl rhein to be precipitated out from than heavy phase.Throw out is after filtration also with softening water flush away vitriol.Productive rate 88% (being) in the used thick diacetyl rhein that comes by step d).The step f) recrystallization, dry and grinding variation pattern A
Under stirring fast, will be suspended in by the 7.5kg diacetyl rhein (referring to dry-matter) of step e) gained in 250 liter of 90% (volume) ethanol.Suspension is heated to 70 ℃, mixes with the 3.75kg potassium acetate then.Be cooled in 0-2 ℃, the crystallization from the settled solution that forms simultaneously of pure diacetyl rhein sylvite goes out.Leaching sylvite and liquid under the 20-30 ℃ of temperature in 800 liter of 48% (volume) ethanol, it is 3.0 that settled solution is transferred its pH value with 10% (weight) sulfuric acid.The diacetyl rhein that crystallization is gone out leaches and removes vitriol with the softening water washing.Variation pattern B
The 7.5kg diacetyl rhein is suspended in 275 liters of ethyl lactates, under heating, makes it become solution, in 20-25 ℃ of stirring, filter and crystallization.The diacetyl rhein that crystallization is gone out filters and washs with softening water.
At first with product in the 1mbar vacuum, 40 ℃ dry 24 hours down.When content of residual water is reduced to 3% when following, this material is by sticking broken and in 70 ℃ in 1mbar vacuum further dry 24 hours down roughly.After this, be ground into the screening size and be 0.5mm, dry to remove solvent residues down in 70 ℃ in 1mbar vacuum again.The productive rate that obtains from step f) is 95%.Embodiment 2
Repeat embodiment 1 described method, just done following change:
In the extraction process of sennae medicine, use trisodium citrate, wherein the 2.85kg trisodium citrate is joined in this medicine of 40kg before adding solvent.What use as solvent is to be heated to 60 ℃ 70% methyl alcohol, behind the methyl alcohol of removing 11.4 liters of volumes, this enriched material is mixed with about 2 liters of fourths-2-is pure.
The reduction of sennae fruit enriched material/fourth-2-alcohol mixture divided for 7 steps finished at nitrogen under as the situation of protection gas.After reduction step 1, then carry out the precipitation of thick yellow acid-9-anthrone-8-glucoside.The reduction step II is used for part to VII and removes aloe---emodin derivates.These steps are carried out under the nothing precipitation.The last precipitation of the rhubarb yellow-9-anthrone-8-glucoside of purifying occurs in after the last reduction step.The reduction step I:
100 liters of sennae fruit enriched material/fourth-2-alcohol mixtures that contain the 4kg sennoside are placed in the container of belt stirrer and and cover with nitrogen.When stirring, 6 liter of 20% (weight) oxygen aqueous solution of sodium oxide and the saturated fourth-2-alcohol (for example adverse current is from rapid II) of 350 premium on currency are added wherein successively, then stirred 15 minutes.This batch materials is heated to 42-50 ℃, and mixes, further stirred subsequently 45 minutes with the 7kg V-Brite B.Make PH remain on 7.5-8 with 20% (weight) aqueous sodium hydroxide solution.Reducing power (to the Ag/AgCl electrode) if necessary maintains by adding V-Brite B-630mV under.After being cooled to 30-35 ℃, transferring its PH＜4 and in 1.5 hour time, finishing precipitation with 10% (weight) sulfuric acid.The suspended substance that obtains was stirred 10 hours under low stirring velocity being lower than under 25 ℃ of temperature.The throw out that obtains is filtered out.This throw out is suspended in the fourth-2-alcohol of 60 liter 15% (weight), stirred 30 minutes down, filter then at 50-60 ℃.With 100 liters of softening water washing residual solution.The thick productive rate of rhubarb yellow-9-anthrone-8-glucose is greater than 82%, (with respect to used sennoside).The reduction step II:
Thick yellow acid-9-anthrone glucoside that 3.3kg is come by the step I is suspended in the mixture of 42 liters of softening waters and 7.4 liters of fourth-2-alcohol.This suspension and 2 liter of 20% (weight) aqueous sodium hydroxide solution and 9.9kg trisodium citrate form solution, after this mix with the saturated fourth-2-alcohol (for example adverse current is from the step III) of 3.3kg V-Brite B and 350 premium on currency.This batch materials is heated to 42-45 ℃.Its pH value maintains 8.5-9 with 20% (weight) aqueous sodium hydroxide solution, if necessary, reducing power (to the Ag/AgCl electrode) maintains by adding polythionic acid sodium (Sodium thoinite)-750mV under.
After leaving standstill 30 minutes, the upper strata to be removed mutually, lower floor is further used in the step III mutually.The reduction step III:
By adding the described reduction of lower floor's phase repeating step II that following chemical will come from the step II:
1.65kg V-Brite B
0.8 noon 20% (weight) aqueous sodium hydroxide solution
The saturated fourth of 350 premium on currency-2-alcohol (for example adverse current is from the step IV) reduction step IV-VII:
By adding the described reduction/extracting process of lower floor's phase repeating step II that following chemical will come from each step:
0.825kg V-Brite B
0.4 rise 20% (weight) aqueous sodium hydroxide solution
The saturated fourth of 350 premium on currency-2-alcohol (for example adverse current is from following step)
To in the step VII, isolating lower floor be cooled to 30-35 ℃ mutually, rhubarb yellow-9-anthrone-8-glucoside will be settled out with the described method of step I.With the sedimentation and filtration that obtains, with 200 liters of softening water washings.Then.Cover (its preparation is referring to the step B of embodiment 1) with 10 liters of ferrum sulfuricum oxydatum solutums.
With embodiment 1 described method rhubarb yellow-9-anthrone-8-glucoside is converted into diacetyl rhein then.Drug test
The effect of diacetyl rhein can determine in the chronic inflammatory diseases analogue body behind oral administration.Following test simulation body is such: cotton balls shape granuloma of mouse and the joint disease of rabbit are induced by the intra-articular injection vitamin A.A) the cotton balls shape granuloma of mouse
Give 25,50 or 100mg diacetyl rhein/kg or 5mg INDOMETHACIN/kg or 100mg/ Asprin/kg continuous 5 day every day with young sexual maturity mouse (n=10).Control group is application of water only.The granuloma of implanting is in appearance in first day of treatment.When off-test, the granulomatous fresh and withered weight of manufacturing is compared with control group according to different dosages and is shown significantly, reduces greatly.The activity of 100mg diacetyl rhein/kg is equivalent to the activity of 5mg INDOMETHACIN or 100mg Asprin.Thymus gland and adrenal weight do not change when treatment.B) vitamin A joint disease:
Resemble joint disease that the joint changes and be in two groups every group 10 rabbits (white New Zealand's kind (New Zealander)) 9 days by three intrinsic articulations injections 30,000IU vitamin A.After 56 days, 10 animals were treated for 8 weeks with 3mg diacetyl rhein/kg/ days.Compare with control group, other joint of debating of the macroscopic and microscopy of treatment group changes decline greatly.
In addition, the therapeutic activity of diacetyl rhein and the therapeutic activity of Asprin are compared with every group of 7 rabbits, these rabbits are with three times 10,000IU vitamin A pre-treatment 6 days and do not have treatment in 8 interior 26 days of weeks and handle allows them use 5mg diacetyl rhein/kg/ days (test group) or 15mg Asprin/kg/ days (positive controls) or keeps not treating (negative control group).In these three groups, after the injection of last vitamin A 24 days, similarly ataxia occurs with the dilatory form of back leg.In negative control group, in 8 weeks afterwards, significantly the sacroiliitis clinical symptom increases the weight of.In test group and positive controls, these symptoms are improved greatly during the treatment of 8 weeks.Mucous gastritis changes
Although independent use 400mg diacetyl rhein/kg or solvent can not make the stomach mucous membrane of mouse produce any erosion, but after using ibuprofen (20mg/kg) or INDOMETHACIN (20mg/kg), but can find the tangible gastric mucosa injury of point-like (1mm diameter) to the rotten to the corn form of big area (3mm diameter).In 3 days every day 100mg diacetyl rhein/kg of twice administration do not cause any gastric mucosa injury yet, and correspondingly use 10mg INDOMETHACIN/kg to produce the erosion of 1-3mm diameter really.Toxicity test
Acute toxicity LD50 depends on the animal species (rat, mouse, cat) of test, and rat is least responsive to this behind oral 1.9-7.9g/kg.Under the administered parenterally situation (i.v. or i.p.), its LD50 is 119-339mg/kg for the animal of these kinds.Clinical trial
1, the activity of diacetyl rhein is tested in 95 (49/46) patients that suffer from coxitis and gonitis, the patient be in the double blind trial with use naproxen and after treatment the use placebo methods of treatment as a comparison.The dosage of medicine is twice 50mg diacetyl rhein or 750mg naproxen once a day every day.The cycle of treatment be 60 days that washed after date in 7 days at 1.Thereafter placebo treatment continues 60 days again.
Test parameter is the pain and the motor symptoms of the form of keeping the score, the function limit and adaptability.
In these two treatment groups (in the diacetyl rhein/naproxen), all test parameters are compared with original value and have been shown that all statistical tangible improvement rate (being respectively p＜0.01 and p＜0.05) is after cutting off treatment and follow-up placebo administration, at 90 days and 120 days, spontaneous pain was compared with the situation that the naproxen/ placebo is used in combination with the parameter of active and passive movement pain and is shown statistical clear superiority (p＜0.01).This difference can by stop the diacetyl rhein administration after 30 days night pain and the difference in change of pressurized pain 5% proved.
2, in the open continuous research that contrast is arranged, in 70 (35/35) patients, done the test of diacetyl rhein to backbone and gonarthrosis treatment.The amount of penetrating of giving is 100mg diacetyl rhein every day.Treatment cycle is 60 days, and the observation cycle is 75 days.Test parameter is pain and limit of sports record.These parameters are according to the score system evaluation.
The control group of being made up of 35 patients is only taked physical therapy measures, and physiotherapy is also implemented diacetyl rhein treatment group.
According to all parameters, evaluation of result has shown that the treatment group has statistical clear superiority than control group.After treatment finished, successive result of treatment (hang-over n. effect) can be verified in the diacetyl rhein group in addition.
3, diacetyl rhein is to carry out the blind chiasma type research trial of list in 20 patients under with naproxen situation in contrast to the activity of local arthritis example.In the test patient is divided into 2 groups: in first group, initial administration 50mg diacetyl rhein one day twice totally 20 days.Then, three days flush period are arranged, use one day two treatments of 250mg naproxen 20 days then.In second group, this program is put upside down use.Treatment cycle amounts to 43 days.According to score system determination test parameter, it comprises: pain, compressing pain, passive movement pain, the function limit and swelling.
Evaluation result has shown with diacetyl treatment and the advantage of comparing with the naproxen treatment.Do not observe the side effect and its clinical trial parameter that are worth record and do not have variation yet.
4, in 23 (12/11) osteoarthritis patients, test the activity of diacetyl rhein with irregular double-blind study with " two art prostheses " (Study on Compatibility).Dosage be every day twice 50mg diacetyl rhein and every day three 250mg naproxen.Treatment cycle was 4 weeks.Obtain in the Esophagogastric duodenoscopy of test parameter before and after treatment.Only find that in this research the patient has normal mucous membrane or slight stomach to damage (1 grade).
After 4 weeks, splanchnoscopy finds only to have in the group with the diacetyl rhein treatment example (10%) to find that 2 grades of stomach mucous membranes damage, yet, in group, but there are 5 patients (50%) to find that 2,3,4 grades of stomach mucous membranes damage with the naproxen treatment.In all tests, can find that all the normal patient who absorbs exists.
In separating funnel, make the 50mg diacetyl rhein be dissolved in the 0.5M aqueous sodium hydroxide solution of 25.3ml and broadcast 10 minutes.Then the solution that contains 0.5M glycine and 0.5M sodium-chlor with 74.6ml adds wherein, and the pH value that obtains solution thus is 9.5.
25ml chloroform extraction 3 times of this solution.The organic phase of collecting extracts 1 time with buffer reagent (glycine, sodium hydroxide and the sodium-chlor) extraction 1 time of the PH9.5 of 10ml0.5M with 10ml0.01M sulfuric acid.Solvent is removed from organic phase, and resistates is dissolved in the 1ml methyl alcohol.
Standardized solution is that the 2mg rhabarberone is dissolved in 20m1N, in the N-N,N-DIMETHYLACETAMIDE and to be diluted to solubility with methyl alcohol be 2 μ g/ml, is equivalent to 40ppm and obtains.
The content of solution is measured with HPLC.The consistence of HPLC method is to use aloe---the Schuttgelb standardized solution illustrates that the concentration range of said standardized solution is to 53.6 μ g/ml (being equivalent to 1072ppm) from 0.11 μ g/ml (being equivalent to 2.2ppm).Assay loads with 5 μ m Lichrospher-100RP-18 in the post with Merck HPLC column Lichrocart250-4, and temperature is 40 ℃, and moving phase contains 1% acetate methanol solution (V/V).1% acetic acid aqueous solution (V/V) and acetonitrile (its ratio is 49: 46: 5).
Claims (18)
1. the method for preparing diacetyl rhein, the diacetyl rhein that wherein contains aloe-Schuttgelb component is at C
4-C
5Alkanol or C
1-C
3Dialkyl ketone and pH carry out liquid-liquid partition between the water of 6.5-7.5, reclaim diacetyl rhein and the optional recrystallization that carries out.
2. method according to claim 1 is characterized in that:
A) rhubarb yellow-9-anthrone-9-glucoside that will contain aloe-Schuttgelb component is oxidized to corresponding anthraquinone compounds,
B) glucose residue on 8 of the anthraquinones is divided in acidic medium,
C) will obtain 1, the acetylize of 8-dihydroxy-anthracene naphtoquinone compounds, and
D) with the product that obtains at C
4-C
5Alkanol or C
1-C
3Dialkyl ketone and pH carry out liquid-liquid partition between the water of 6.5-7.5, reclaim diacetyl rhein and the optional recrystallization that carries out.
3. method according to claim 1 is characterized in that:
A) the sennoside mixture is reduced into corresponding anthrone compound,
B) the anthrone compound oxidation that obtains is become corresponding anthraquinone compounds,
C) glucose residue on 8 of the anthraquinones is divided in acidic medium,
D) will obtain 1, the acetylize of 8-dihydroxy-anthracene naphtoquinone compounds, and
E) with the product that obtains at C
4-C
5Alkanol or C
1-C
3Dialkyl ketone and pH carry out liquid-liquid partition between the water of 6.5-7.5, reclaim diacetyl rhein and the optional recrystallization that carries out.
4. according to any one described method among the claim 1-3, wherein carry out liquid-liquid partition with fourth-2-ketone.
5. according to any one described method among the claim 1-3, wherein contain water and carry out liquid-liquid partition with the acetic ester buffered.
6. method according to claim 4 wherein contains water with the acetic ester buffered and carries out liquid-liquid partition.
7. according to any one described method in claim 1-3 and 6, wherein liquid-liquid partition carries out with reflux type.
8. method according to claim 4, wherein liquid-liquid partition carries out with reflux type.
9. method according to claim 5, wherein liquid-liquid partition carries out with reflux type.
10. method according to claim 2, wherein trivalent iron salt is as oxygenant.
11. method according to claim 10, wherein trivalent iron salt is a ferric sulfate.
12. method according to claim 3, wherein the sennoside mixture can be by obtaining with aqueous methanol extraction sennae medicine.
13. method according to claim 12 is wherein carried out methanol extraction in the presence of buffer reagent.
14. method according to claim 3 wherein uses the SODIUM HYDROSULPHITE an alkali metal salt as the reductive agent in the step a).
15. method according to claim 14, wherein reduction reaction is to carry out under the condition of 7-9 at pH.
16. method according to claim 3, wherein reduction reaction repeats.
17. according to any one described method among the claim 1-3, the diacetyl rhein that wherein obtains is dissolved in moisture C by converting it into
1-C
3An alkali metal salt in the alcohol and carry out recrystallization and add acid and diacetyl rhein is precipitated once more.
18. according to any one described method among the claim 1-3, wherein diacetyl rhein carries out recrystallization with ethyl lactate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92115357 CN1046700C (en) | 1992-12-19 | 1992-12-19 | Reduction of the sennoside mixture to the corresponding anthrone compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92115357 CN1046700C (en) | 1992-12-19 | 1992-12-19 | Reduction of the sennoside mixture to the corresponding anthrone compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1088571A CN1088571A (en) | 1994-06-29 |
| CN1046700C true CN1046700C (en) | 1999-11-24 |
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ID=4947347
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92115357 Expired - Lifetime CN1046700C (en) | 1992-12-19 | 1992-12-19 | Reduction of the sennoside mixture to the corresponding anthrone compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1046700C (en) |
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1992
- 1992-12-19 CN CN 92115357 patent/CN1046700C/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| CN1088571A (en) | 1994-06-29 |
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