CN101423537A - Scutellarin and medical use thereof - Google Patents
Scutellarin and medical use thereof Download PDFInfo
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- CN101423537A CN101423537A CNA2007101766624A CN200710176662A CN101423537A CN 101423537 A CN101423537 A CN 101423537A CN A2007101766624 A CNA2007101766624 A CN A2007101766624A CN 200710176662 A CN200710176662 A CN 200710176662A CN 101423537 A CN101423537 A CN 101423537A
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Abstract
The invention relates to a scutellarin ester, a synthesis preparation method thereof, and medical application of the scutellarin ester to treating cerebral ischemia. The structure of a scutellarin ester compound is shown by formula I, wherein R represents C1-C15 chain fatty alcohol, ring fatty alcohol and substituted fatty alcohol such as methanol, alcohol, amyl alcohol, cyclopentanol, cyclohexanol, benzoic alcohol, phenylethyl alcohol, and the like, or C1-C10 fatty diol such as 1,4-butylene glycol, or C1-C10 fatty triol such as glycerol, or phenols such as phenol, p-cresol, naphthol, and the like. The compound can be obtained through the following step: under the acid catalysis, the scutellarin ester reacts with the hydroxy in the alcohol or phenol compounds at a nomal temperature or in a heating and refluxing status so as to obtain the compound. The derivative and a pharmaceutically acceptable carrier form a medicine compound. The preparation method for the medicine compound is as follows: the scutellarin ester is evenly mixed with pharmaceutically acceptable supplementary materials to prepare the required dosage form. The scutellarin ester can be absorbed through oral administration, and has an obvious improvement function on rats with middle cerebral artery focal cerebral ischemia.
Description
Technical field
The invention belongs to the traditional Chinese medicine research field, be specifically related to class scutellarin and preparation method thereof, this derivative or its pharmaceutical composition medical use aspect the cerebral ischemia treatment.
Technical background
Breviscarpine (scutellarin) is the flavonoids effective constituent that extracts from composite family bitter fleabane platymiscium Erigeron breviscapus (Vant.) Hand.-Mazz. (Erigeron breviscapus (Vant.) Hand.-Mazz.), its main active ingredient (about more than 70%) is a scutellarin, promptly 4 ', 5,6-trihydroxyflavone-7-O-β-D-glucuronide claims scutellarin again.Pharmacological research show Breviscarpine can vasodilation, increase heart coronary flow, cerebral blood flow increasing amount, reduce cerebral vascular resistance, improve the effects such as platelet aggregation that blood-brain barrier permeability and antagonism are caused by adenosine diphosphate (ADP).Be mainly used in treatment of diseases such as apoplexy sequela, coronary heart disease, stenocardia clinically, determined curative effect.
The formulation of Breviscarpine listing at present has multiple, and injectable dosage forms has powder injection, lyophilized powder, infusion preparation and lipidosome freeze-dried injection; Oral dosage form has conventional tablet, soft capsule, dripping pill, dispersible tablet, controlled release tablet etc.
Breviscarpine is a flavonoid glycoside compound, shows because of its planar chemical structure that it is water-soluble and fat-soluble all relatively poor.Absorb in the Breviscarpine drug administration by injection body fast, the transformation period is short, eliminate rapidly in the body, the effective blood drug concentration weak point of holding time.Particularly the bioavailability of oral Breviscapine is very low, and the report in the GCP of family base all shows almost and can't detect scutellarin in vivo surplus in the of ten, and therefore the result of treatment to oral route has produced query.
Medicine as stroke in convalescent stage, patient's more options are in and are received treatment, add increasing the untoward reaction of Breviscarpine injection at present, drug administration by injection is not the optimal selection of such disease treatment, and there are the extremely low problem of oral administration biaavailability in convenience, inexpensive oral Breviscapine at present.In order to overcome above-mentioned shortcoming, keep the clinical efficacy of medicine simultaneously, make things convenient for medication, we start with from the absorption that improves medicine, scutellarin is carried out structural modification and screening active ingredients evaluation, and find that its ester derivative can overcome the extremely low defective of its bioavailability.
The carboxyl that the present invention is directed on 7 glucuronic acids in the scutellarin molecule carries out a series of esterification, has improved the physico-chemical property and the perviousness of former medicine, has improved its oral administration biaavailability.
The patent of relevant Breviscarpine application has 82, and wherein design patent is 7,75 of patents of invention, and the disclosure of the Invention content relates generally to formulation preparation technology and methods such as Herba Erigerontis tablet, infusion preparation, dripping pill and granule.Patent about the scutellarin derivative is not appeared in the newspapers.
Summary of the invention
The object of the present invention is to provide the scutellarin ester compound.
The object of the present invention is to provide the synthesis preparation method of scutellarin ester compound.
The pharmaceutical composition that the object of the present invention is to provide scutellarin and form with pharmaceutically acceptable carrier.
The object of the present invention is to provide scutellarin or its pharmaceutical composition medical use aspect the cerebral ischemia treatment.
Embodiment
For overcome in the Breviscarpine drug administration by injection body absorb fast, the transformation period is short, eliminate rapidly in the body, the effective blood drug concentration weak point of holding time, the oral preparations bioavailability is extremely low, almost non-absorbent defective, the present invention adopts esterification process that scutellarin is carried out structural modification, modify point and be the carboxyl in the scutellarin structure, with stop glucuronic acid lytic enzyme in the drug absorption process to the enzymolysis of scutellarin (because of its enzymolysis product 4 ', 5,6, the 7-kaempferol is extremely unstable), improve its oral administration biaavailability.
For achieving the above object, the present invention is implemented by following technical proposals.
Scutellarin shown in the one class general formula I, it is characterized in that: R is chain fatty alcohol, cycloaliphatic alcohol, the replacement Fatty Alcohol(C12-C14 and C12-C18) of C1～C15, as methyl alcohol, ethanol, amylalcohol, ring propyl alcohol, hexalin, benzylalcohol, phenylethyl alcohol etc., or the aliphatic dialcohol of C1-C10, as 1,4-butyleneglycol etc., the perhaps fatty triol of C1-C10, as glycerine etc., perhaps phenols is as phenol, p-cresol, naphthols etc.
General formula I
Described scutellarin, its preparation method be scutellarin under acid catalysis, react under reflux (or microwave-assisted) state with the hydroxyl of alcohol or phenolic compound, extraction, recrystallization prepares.
Described scutellarin, used acid is organic acid or the mineral acid that pharmaceutically allows in its preparation process, preferred hydrogenchloride (gas), the vitriol oil, tosic acid.
Described scutellarin, alcohol or phenolic compound used in its preparation process are that R is chain fatty alcohol, cycloaliphatic alcohol, the replacement Fatty Alcohol(C12-C14 and C12-C18) of C1～C15, as methyl alcohol, ethanol, amylalcohol, ring propyl alcohol, hexalin, benzylalcohol, phenylethyl alcohol etc., or the aliphatic dialcohol of C1-C10, as 1,4-butyleneglycol etc., the perhaps fatty triol of C1-C10, as glycerine etc., perhaps phenols is as phenol, p-cresol, naphthols etc.
Described scutellarin can react preferred 50-110 ℃ under reflux (or microwave-assisted) state in its preparation process.
Above-mentioned scutellarin and pharmaceutically acceptable carrier form pharmaceutical composition.
Described pharmaceutical composition, its formulation are any formulation that pharmaceutically allows, and are generally tablet, capsule, granule, powder, microcapsule, pill, pill, injection etc.
Described preparation of drug combination method is that scutellarin and mixing acceptable accessories is even, and common process is made required formulation.
Described scutellarin can be converted into scutellarin in vivo by oral absorption.
Described scutellarin has remarkable therapeutic action to the intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia.
Help to understand the present invention by following example, but can not limit content of the present invention.
Synthesizing of embodiment 1 scutellarin methyl esters
Scutellarin is dissolved in an amount of methyl alcohol, under the catalysis of concentrated hydrochloric acid, is heated to boiling, keep slight boiling condition, reaction 3h, TLC monitoring reaction process is after reaction finishes, organic solvent extraction, reclaim solvent, again with dissolve with methanol, room temperature is carried out recrystallization, get the pure product of scutellarin methyl esters, yield 85%-95%.Faint yellow needle crystal, mp250 ℃ (dec); Molecular formula is C
22H
20O
12, ESI-MS provides quasi-molecular ion peak m/z 477.4[M+H]
+ 1H-NMR (DMSO-d
6): δ 12.76 (1H, br.s, 5-OH), δ 10.37 (1H, br.s, 4 ' OH), and δ 8.60 (1H, br.s, 6-OH), δ 7.92 (2H, d, 2 ', 6 '-H), δ 6.93 (2H, d, 3 ', 5 '-H), δ 7.08 (1H, s, 8-H), δ 6.81 (1H, s, 3-H), δ 3.76 (3H, O
CH 3 ).
Synthesizing of embodiment 2 scutellarin ethyl esters
Scutellarin is suspended in the dehydrated alcohol, adds an amount of acid, reflux 3h, TLC monitoring reaction process, after reaction finishes, NaHCO
3Regulate the pH value, organic solvent extraction reclaims solvent, and again with dissolve with ethanol, room temperature is carried out recrystallization, gets the pure product of scutellarin ethyl ester, yield 85%-96%.Faint yellow needle crystal, mp:257-259 ℃; Molecular formula is C
23H
22O
12, ESI-MS provides quasi-molecular ion peak m/z 491.2[M+H]
+1738cm in the infrared spectra (FT-IR)
-1Be the absorption peak of ester carbonyl group, 1664cm
-1Absorption peak for C-4 position association carbonyl;
1H-NMR (DMSO-d
6) provide 22 hydrogen proton signals, and δ 12.73 (1H, br.s, 5-OH), δ 10.36 (1H, br.s, 4 ' OH), and δ 8.61 (1H, br.s, 6-OH), δ 7.93 (2H, d, 2 ', 6 '-H), δ 6.94 (2H, d, 3 ', 5 '-H), δ 7.0 (1H, s, 8-H), and δ 6.8 (1H, s, 3-H), δ 5.52 (1H, d, glc-1-H), δ 1.2 (3H, t ,-CH
2-
CH 3 ).
Synthesizing of embodiment 3 scutellarin isopropyl esters
Scutellarin is suspended in the anhydrous isopropyl alcohol, adds an amount of acid, reflux 4h, TLC monitoring reaction process after reaction finishes, obtains purity and is 80% scutellarin isopropyl ester product, with recrystallizing methanol twice, get the scutellarin isopropyl ester of purity 95%, yield about 40%.Faint yellow needle crystal, mp:250-251 ℃; Molecular formula is C
24H
24O
12, ESI-MS provides quasi-molecular ion peak m/z 505.2[M+H]
+1737cm in the infrared spectra
-1Be the absorption of ester carbonyl group (medium tenacity), simultaneously, the carbonyl absorption (1720-1680cm on the carboxyl
-1) disappear.
1H NMR shows in the molecule 24 protons, wherein δ 1.1-1.2 (6H, 2 * CH
3) be proton on two methyl of sec.-propyl, (1H m) connects proton on the oxygen carbon for sec.-propyl to δ 4.91-4.98.
Synthesizing of embodiment 4 scutellarins-4 '-hydroxyl butyl ester
Scutellarin is dissolved among the THF in right amount, add an amount of 1, the 4-butyleneglycol, under sulphuric acid catalysis, with 1, the 4-butyleneglycol reacts 4h under cold condition, obtain purity and be scutellarin-4 '-hydroxyl butyl ester product of 80%, recrystallizing methanol gets scutellarin-4 '-pure product of hydroxyl butyl ester, yield 75%.Needle crystal; Molecular formula is C
25H
26O
13, positively charged ion ESI-MS provides quasi-molecular ion peak m/z 535.4[M+H]
+ 1H NMR and scutellarin
1H NMR compares, and has had more the signal of the proton hydrogen of 4 '-hydroxybutyl.
Synthesizing of embodiment 5 scutellarin glyceryl ester
Scutellarin is dissolved among the THF in right amount, adds an amount of glycerine, under acid catalysis, and reflux 4h (TLC monitoring reaction process), after reaction finishes, in the mixture impouring frozen water, organic solvent extraction, recrystallization, the scutellarin glyceryl ester of purity 98%, yield about 40%.Needle crystal; Molecular formula is C
24H
24O
14, positively charged ion ESI-MS provides quasi-molecular ion peak m/z 537.4[M+H]
+ 1H NMR and scutellarin
1H NMR compares, and has had more the signal of glyceryl proton hydrogen, i.e. four even the hydrogen proton on the oxygen carbon and the signals of reactive hydrogen.
Synthesizing of embodiment 6 scutellarin benzyl esters
Scutellarin (1moL) is suspended among the anhydrous MDF, adds benzylalcohol (1.2moL) and an amount of acid, the about 4h of reflux (TLC monitoring reaction process), after reaction finishes, in the impouring frozen water, filter, recrystallization, the scutellarin benzyl ester of purity 98%, yield about 70%; Needle crystal, mp:285-287 ℃; Molecular formula is C
29H
26O
12, ESI-MS:m/z 565.2[M-H]
- 1H NMR (DMSO-d
6): (5-OH), 10.38 (4 ' OH) for 1H, s for 1H, s for δ 12.72,8.58 (1H, s, 6-OH), 7.85 (2H, d, J=8.5Hz, 2 ' H, 6 ' H), 6.99 (1H, s, 8-H), 6.90 (2H, d, J=8.5Hz, 3 ' H, 5 ' H), 6.81 (1H, s, 3-H), 7.27-7.38 (5H, m ,-ph), 5.12 (2H, br.s ,-ph-
CH 2 -).
Synthesizing of embodiment 7 scutellarin phenyl esters
Scutellarin (1moL) is suspended in an amount of dimethyl formamide, add bromobenzene (1.2moL) and an amount of Hydrogen bromide, the about 2h of reflux (TLC monitoring reaction process), after reaction finishes, in the reaction mixture impouring frozen water, ethyl acetate extraction, extraction liquid is recycled to dried, dissolve with methanol, recrystallization, the scutellarin phenyl ester of purity 98%, yield about 55%; Needle crystal, mp:223-226 ℃; Molecular formula is C
28H
24O
12, ESI-MS:m/z551.2[M-H]
- 1H NMR (DMSO-d
6): δ 12.72 (1H, s, 5-OH), 10.38 (1H, s, 4 ' OH), 8.59 (1H, s, 6-OH), 7.88 (2H, d, J=8.8Hz, 2 ' H, 6 ' H), 6.99 (1H, s, 8-H), 6.91 (2H, d, J=8.8Hz, 3 ' H, 5 ' H), 6.81 (1H, s, 3-H), 7.27-7.38 (5H, m ,-ph).
Embodiment 8 scutellarins are to the influence of intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia
Medicine and reagent
Scutellarin: purity 95%; Scutellarin ethyl ester: purity 95%; The scutellarin isopropyl ester: purity 95%, three sample all adds the pH6.8 phosphate buffered saline buffer suspendible of different volumes before administration every day, be made into desired concn.
Experimental technique and result
Get 40 of the healthy male SD rats of body weight 130～150g, be divided into 4 groups at random, be i.e. model control group, scutellarin group (positive drug group), scutellarin ethyl ester group, scutellarin isopropyl ester group, 10 every group by body weight.Gastric infusion, scutellarin group, scutellarin ethyl ester group, scutellarin isopropyl ester group dosage are 50mg/kg, and the administration volume is 1mL/100g, administration every day 1 time, successive administration 7 days.Model control group is given equal-volume physiological saline.Each organizes rat behind the 6th day administration 1h, abdominal injection 10% Chloral Hydrate (350mg/kg) anesthesia.Press methods such as Tamura
[1,2]Right arm reclining is fixed, do an arc incision at the eye corner of the eyes and external auditory meatus midline, be about 1.5cm, pinch off temporalis and excision, bite away zygomatic arch with rongeur, expose the squamosal bone major part, about 2mm holes with dental burr at the place below uniting before zygomatic arch and squamosal bone then, open an about 2mm diameter microcephalia window, expose arteria cerebri media.There is 50% liquor ferri trichloridi (with the preparation of 1mol/L hydrochloric acid) 10ul to drop on the small pieces filter paper suction, apply at this section of rat arteria cerebri media place, remove filter paper behind the placement 30min, use the normal saline flushing local organization, layer-by-layer suture steams again behind the conventional skin degerming and raises.The surgical procedure room temperature is controlled at 23～25 ℃.Postoperative (23h after the modeling) on the secondth continues administration 1 time.The 24h broken end is got brain after modeling.
Influence to neurosigns
Get administration according to the method described above and modeling and respectively organize rat, carry out the behavior scoring of nervous symptoms in postoperative 6h and 24h.Method is as follows: 1. carry the mouse tail and observe forelimb flexing situation, stretch to ground, count 0 fen as two forelimb symmetries, as the offside forelimb of operation occur that wrist is bent, elbow flexing, shoulder inward turning or existing wrist elbow flexing have shoulder inward turning person again, counts 1,2,3,4 fen respectively.2. animal is placed on the level land, push away both shoulders respectively, check resistance to side shifting, as bilateral resistance equity and strong, count 0 fen, resistance descender when promoting as offside to operation, according to decline degree difference be divided into gently, in, weigh three degree, count 1,2,3 fen respectively.3. the two forelimbs of animal are put on the wire netting, observed two muscle of anterior limb tension force.Two muscle of anterior limb tension force equities and strong person count 0 fen, count 1,2,3 fen according to operation offside limb tension force decline degree difference equally.4. animal has and does not stop counting 1 fen to a side person of turn-taking, and according to standards of grading, full marks are 11 minutes, and mark is high more, and the animal behavior obstacle is serious more.
The result shows that according to the study of behaviour standards of grading, each organizes rat 6h, 24h appearance neurosigns in various degree after modeling.Compare with model group, each administration group all can reduce the behavior scoring that the arteria cerebri media embolism causes rats with cerebral ischemia to some extent, 6h after modeling, scutellarin group, scutellarin ethyl ester group, scutellarin isopropyl ester group and model group relatively there is no significant difference; 24h after the modeling, scutellarin group, scutellarin ethyl ester group, scutellarin isopropyl ester group and model group more all have significant difference; Scutellarin ethyl ester group and scutellarin isopropyl ester group are better than the scutellarin group to the improvement effect of neurosigns, have compared significant difference with the scutellarin group; The effect of scutellarin ethyl ester group is better than scutellarin isopropyl ester group slightly, but both compare there was no significant difference.See Table 1.Be scutellarin to the intensity that influences of rat nervous symptoms behavior scoring due to the arteria cerebri media embolism be lamp-dish flower acetic ethyl ester 〉=lamp-dish flower acetic isopropyl ester〉scutellarin.
Table 1 scutellarin and derivative thereof to the influence of arteria cerebri media embolism rat neurosigns (x ± s, n=10)
Annotate: rank test, compare with model group: * p＜0.05, * * p＜0.01,
Compare with the scutellarin group: #p＜0.05, ##p＜0.01.
Influence to the cerebral infarction scope
Get administration as stated above, modeling and carry out 4 groups of rats of postoperative 24h behavior scoring, every group 10, the difference sacrificed by decapitation, take out full brain rapidly, remove olfactory bulb, cerebellum and low brain stem, left and right brain separates, and crown 3 cuttves of cutting divide 4 under 0-4 ℃ respectively, rapidly the brain sheet is placed TTC dyeing (the contained 4%TTC 1.5ml of every 5ml dye liquor, 1mol/LK
2HPO
40.1ml), 37 ℃ of lucifuge temperature are incubated 30min, take out to be placed on the 24h that keeps in Dark Place in 10% formaldehyde solution.The non-ischemic region in dyed back is a rose, and infarct is a white.The white infarct kitchen range carefully dug down weigh, the per-cent that accounts for total brain weight with infarction tissue's weight calculates the cerebral infarction scope of every animal respectively, the comparative group differences as the cerebral infarction scope.The left side brain is a blank.
The result shows, compares with blank, and the white cerebral infarction zone of obvious different area all appears in each cerebral tissue of organizing rat.With model group relatively, scutellarin group, scutellarin ethyl ester group, scutellarin isopropyl ester group all can minimizing intraluminal middle cerebral artery occlusion in rats embolism in various degree due to the weight percent of infarction size, significant difference; Compare with the scutellarin group, scutellarin ethyl ester group and the effect of scutellarin isopropyl ester group obviously are better than scutellarin group, significant difference; Compare with scutellarin ethyl ester group, the effect of scutellarin isopropyl ester group is weaker than scutellarin ethyl ester group, significant difference; Be scutellarin to the intensity that influences of rat cerebral infarction scope due to the arteria cerebri media embolism be the lamp-dish flower acetic ethyl ester〉the lamp-dish flower acetic isopropyl ester〉scutellarin.See Table 2.
Table 2 scutellarin and derivative thereof to the influence of arteria cerebri media embolism rat cerebral infarction scope (x ± s, n=10)
Annotate: T check between group, compare with model group: * p＜0.05, * * p＜0.01,
Compare with the scutellarin group: #p＜0.05, ##p＜0.01.
The plasma sample analysis of embodiment 9 scutellarins
Get 80 of the healthy male SD rats of body weight 130～150g, be divided into 2 groups at random by body weight, be scutellarin ethyl ester group, scutellarin isopropyl ester group, each group is established 8 and is got the blood point, 5 every, each treated animal fasting 12h before the test, irritate stomach respectively and give scutellarin ethyl ester, each 50mg/kg of scutellarin isopropyl ester, the administration volume is 1mL/100g, after administration 30,45,60,90,120,150,180,240min abdominal aortic blood 3.0mL, place the heparinization test tube, 4 ℃ of centrifugal 15min (3000rpm/min) separated plasma.
Get plasma sample 1.0mL and place 10.0mL tool plug test tube, mark (IS) solution (2.50 μ gmL accurate the adding in the 30 μ L rancinamycin IVs
-1), mixing adds ethyl acetate 2.0mL, vortex 2min leaves standstill, and supernatant liquor is transferred in the pyriform bottle, repeating aforesaid operations (is ethyl acetate extraction 3 times 2 times, each 2.0mL), combining extraction liquid, 40 ℃ of evaporated under reduced pressure, residue is with 400 μ L dissolve with methanol, 0.22 μ m millipore filtration filters, sample introduction 20 μ L carry out HPLC and analyze.
Compare by the HPLC color atlas of blank plasma, pastille blood plasma, scutellarin reference substance, scutellarin ethyl ester reference substance and scutellarin isopropyl ester reference substance and the ultraviolet full wavelength scanner figure of chromatographic peak, show that scutellarin ethyl ester and scutellarin isopropyl ester oral administration can be absorbed, and be converted into scutellarin in vivo.
The pharmaceutical composition of embodiment 10 scutellarin ethyl esters
(1) preparation of scutellarin ethyl ester sheet
Effective constituent: scutellarin ethyl ester 20g
Disintegrating agent: croscarmellose sodium 10g
Thinner and dry adhesives: Microcrystalline Cellulose 50g
Weighting agent: lactose 20g
The preparation method: scutellarin ethyl ester and above-mentioned auxiliary material mix by recipe quantity, cross 100 mesh sieves, adopt direct compression process to carry out compressing tablet, make 1000, and every contains main ingredient amount 20mg.General thin dressing and enteric coating that dressing can allow with pharmacy.
(2) the capsular preparation of scutellarin ethyl ester
Effective constituent: scutellarin ethyl ester 20g
Disintegrating agent: sodium starch glycolate 20g
Thinner and dry adhesives: Microcrystalline Cellulose 60g
The preparation method: scutellarin ethyl ester and above-mentioned auxiliary material mix by recipe quantity, cross 100 mesh sieves, and capsule is filled, and makes 1000, and every contains main ingredient amount 20mg.
(3) preparation of scutellarin ethyl ester dripping pill
Effective constituent: scutellarin ethyl ester 20g
Matrix: polyethylene glycol 6000 60g
Macrogol 4000 20g
The preparation method: the scutellarin ethyl ester mixes by recipe quantity with above-mentioned auxiliary material, makes the soup of homogeneous, under the heat-retaining condition routinely dropping method drip system, the dimethyl-silicon oil cooling is made 1000 balls.
Embodiment 11 injection scutellarin ethyl esters
(1) scutellarin ethyl ester 20g
Polysorbate 80 20mL
20% sodium hydroxide
0.1% gac
Water for injection
The preparation method: scutellarin ethyl ester 20g adds the about 950mL of water for injection, addition polymerization sorb ester 8020mL, add 20% sodium hydroxide adjust pH to 7.5, add 0.1% gac heated and boiled 15min, refrigeration 24h filters, filtrate adjust pH to 7.5, add the injection water and make into 1000mL, filter embedding, sterilization, promptly.
(2) scutellarin ethyl ester 20g
95% ethanol 400mL
Propylene glycol 200mL
Phenylcarbinol 20mL
20% sodium hydroxide
1% gac
Water for injection
The preparation method: scutellarin ethyl ester 20g, add the 400mL95% dissolve with ethanol, add the 200mL propylene glycol, add the injection water to 1000mL, add 1% gac, 20% sodium hydroxide adjust pH to 7.5, heated and boiled 15min, refrigeration 24h filters, add phenylcarbinol 20mL, adjust pH to 7.5 adds the injection water to 1000mL, filter, embedding, sterilization, promptly.
The pharmaceutical composition of embodiment 12 scutellarin isopropyl esters
The preparation of 1000g scutellarin isopropyl ester granule
Effective constituent: scutellarin isopropyl ester 20g
Disintegrating agent: sodium starch glycolate 20g
Thinner and dry adhesives: Microcrystalline Cellulose 60g
The preparation method: scutellarin isopropyl ester and above-mentioned auxiliary material mix by recipe quantity, cross 100 mesh sieves, adopt 70% alcohol granulation, dry, whole grain, make 1000g, and every contains main ingredient amount 20mg.
Claims (7)
1. the scutellarin shown in the class general formula I contains the pharmaceutical composition and the medical use aspect the cerebral ischemia disease treatment thereof of this analog derivative.
General formula I
2. the scutellarin shown in the claim 1 formula of I, it is characterized in that: wherein R is chain fatty alcohol, cycloaliphatic alcohol, the replacement Fatty Alcohol(C12-C14 and C12-C18) of C1～C15, as methyl alcohol, ethanol, amylalcohol, ring propyl alcohol, hexalin, benzylalcohol, phenylethyl alcohol etc., or the aliphatic dialcohol of C1-C10, as 1,4-butyleneglycol etc., the perhaps fatty triol of C1-C10, as glycerine etc., perhaps phenols is as phenol, p-cresol, naphthols etc.
3. the preparation method of compound shown in the claim 1 formula of I is characterized in that: scutellarin reacts under normal temperature or reflux state with the hydroxyl of alcohol or phenolic compound under acid catalysis, promptly gets scutellarin.Used acid is organic acid or mineral acid, preferred hydrogenchloride (gas), the vitriol oil, tosic acid.Used alcohol can be methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, amylalcohol, glycerine, benzylalcohol, phenol, p-cresol, naphthols etc.
4. the pharmaceutical composition that contains scutellarin in the claim 1 is characterised in that the pharmaceutical composition that scutellarin and pharmaceutically acceptable carrier form.
5. the described preparation of drug combination method of claim 4 is characterized in that scutellarin and the mixing acceptable accessories in the claim 1 is even, utilizes preparation process to make required formulation.Preferred tablet, capsule, granule, powder, microcapsule, pill, pill, injection etc.
6. scutellarin in the claim 1, it is characterized in that: scutellarin can be converted into scutellarin by oral absorption in vivo as prodrug, overcomes the extremely low defective of scutellarin oral administration biaavailability.
7. scutellarin in the claim 1, it is characterized in that: scutellarin has remarkable therapeutic action to the intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia.
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| CN102391336A (en) * | 2011-09-30 | 2012-03-28 | 昆明制药集团股份有限公司 | Compound and preparation method and use thereof |
| CN101966194B (en) * | 2009-07-28 | 2012-05-30 | 成都中医药大学 | New application of scutellarin and derivatives thereof |
| CN102838645A (en) * | 2012-09-26 | 2012-12-26 | 昆明制药集团股份有限公司 | Polyphenol hydroxy flavone compound with pharmaceutical function and preparation method thereof |
| CN102861342A (en) * | 2011-07-07 | 2013-01-09 | 昆明制药集团股份有限公司 | Scutellarin prodrug using cyclodextrin as carrier and preparation method for scutellarin prodrug |
| CN104910227A (en) * | 2015-06-09 | 2015-09-16 | 中国中医科学院中药研究所 | Amorphous-form scutellarin ethyl ester as well as preparation method and application thereof |
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| CN101966194B (en) * | 2009-07-28 | 2012-05-30 | 成都中医药大学 | New application of scutellarin and derivatives thereof |
| CN102861342A (en) * | 2011-07-07 | 2013-01-09 | 昆明制药集团股份有限公司 | Scutellarin prodrug using cyclodextrin as carrier and preparation method for scutellarin prodrug |
| CN102391336A (en) * | 2011-09-30 | 2012-03-28 | 昆明制药集团股份有限公司 | Compound and preparation method and use thereof |
| CN102391336B (en) * | 2011-09-30 | 2015-04-22 | 昆明制药集团股份有限公司 | Compound and preparation method and use thereof |
| CN102838645A (en) * | 2012-09-26 | 2012-12-26 | 昆明制药集团股份有限公司 | Polyphenol hydroxy flavone compound with pharmaceutical function and preparation method thereof |
| CN102838645B (en) * | 2012-09-26 | 2015-06-17 | 昆药集团股份有限公司 | Polyphenol hydroxy flavone compound with pharmaceutical function and preparation method thereof |
| CN104910227A (en) * | 2015-06-09 | 2015-09-16 | 中国中医科学院中药研究所 | Amorphous-form scutellarin ethyl ester as well as preparation method and application thereof |
| CN114560899A (en) * | 2021-12-22 | 2022-05-31 | 复旦大学 | Preparation method and application of plantain |
| CN114560899B (en) * | 2021-12-22 | 2024-05-14 | 复旦大学 | Preparation method and application of plantain |
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