CN101362791A - Steroidal alkaloid veratramine, preparation method thereof and antihypertensive application - Google Patents
Steroidal alkaloid veratramine, preparation method thereof and antihypertensive application Download PDFInfo
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- CN101362791A CN101362791A CNA200810198639XA CN200810198639A CN101362791A CN 101362791 A CN101362791 A CN 101362791A CN A200810198639X A CNA200810198639X A CN A200810198639XA CN 200810198639 A CN200810198639 A CN 200810198639A CN 101362791 A CN101362791 A CN 101362791A
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Abstract
The invention relates to a veratramine expressed by the following formula (1), which also relates to a preparation method for the veratramine and is characterized in that: dry rootstalks of black hellebore plants are taken as raw materials and are soaked by alkaline solution; after being soaked by chloroform, filter liquid is concentrated into thick paste which is dissolved by dilute acid; the pH value of the filter liquid is adjusted to be 8 to 10 by stronger ammonia water or dilute alkali; the filter liquid is placed for filtering, and sediment is collected and is dissolved by chloroform; a frozen product separated out is swabbed off and becomes powder; chloroform-methanol solution is used for dissolving; dry silica gel column chromatography and recrystallization are carried out to crystals separated out, thus obtaining a product. The invention also relates to an application of the veratramine in preparing drugs for treating high blood pressure; the veratramine has obvious pressure lowering effect on normal animals and animal models with high blood pressure and can slow down heart rate and has tempered and lasting pressure lowering effect and obvious clinically practical value.
Description
Technical field
The present invention relates to a kind of tetrahydroisoquinoline alkaloid, is the veratramin(e) of following formula (1) expression specifically, also relates to preparation method and its application aspect step-down of this compound.
Background technology
Veratrum (VeratrumLinn.) is Liliaceae (Liliaceae) plant, has 40 kinds in the world approximately, and according to " Chinese Plants will " record, there are wherein 13 kinds and a mutation in China.In root and the rhizome of medical RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.), Xingan black false hellebore [V.dahuricum (Turcz.) Loes.f.], temmoku black false hellebore (V.Schindleri Loes.f.), hair fringe black false hellebore (V.maackiiRegel), Dali black false hellebore (V.taliense Loes.f.), hair leaf black false hellebore [V.grane diflorum (Maxim.) Loes.f.] etc. be used as medicine, there are vomiting wind-phlegm by emesis, desinsection to treat the effect of sore, for oral administrationly are used for that apoplexy phlegm is stopped up, cards such as larynx numbness is obstructed, epilepsy; Oil is transferred outer being coated with, and controls the mange favus of the scalp; Also often be used to treat pulmonary tuberculosis and lung cancer, schizophrenia, malaria, fracture etc.
Chinese scholar has been carried out deep research to veratrum alkaloid, and launch research to other chemical ingredients of Veratrum plant recent years again, except that known alkaloid compound, finds stilbene compound, dipeptide, flavonoid and other compounds again.
Black false hellebore root and root stock contain multiple steroidal total alkaloids, and the abundantest with spring and autumn, and summer is minimum.Be mainly veratrine (having another name called veratramin(e)) (Veratramine); fragrant alkali (Jervine) is situated between; pseudojervine (Pseudojervine); the fragrant alkali of red Jie (Rubijervine); Germerine alkali (Germerine) and veratroylzygadenine (Veratroylzygadenine); the fragrant alkali of different red Jie (Isorubi jervine); Protoveratrine A (Protoveratrine A); count not booth alkali (Germidine); two deacetylation Protoveratrine As (Di Deacetylprotoveratrine A); black false hellebore suffering (Verazine); colchicine (Colchicine); veratrine amine first; second; third; fourth (alkamine A; B; C; D); verazine (Verazine), fragrant alkali (Jervine) and neogermbudine (Neogermbudine) etc. are situated between.
In recent years, both at home and abroad from the Veratrum plant isolation identification go out more than 100 kind of tetrahydroisoquinoline alkaloid.In homemade Usu, get each a kind of 7 kinds of different steroidal alkaloids of western veratrum alkaloids and verazine class and barytine Alkaloid the black false hellebore; From Domestic Wool fringe black false hellebore, get 4 kinds of different steroidal alkaloids of western veratrum alkaloids and 2 kinds of verazine Alkaloids; The light arteries and veins black false hellebore that produces from the Changbai Mountain obtains 5 kinds of veratrum alkaloids compounds and 2 kinds of barytine Alkaloids; Composition of getting from the long stalk black false hellebore root that originates from Hubei and black false hellebore similar is the different steroidal alkaloid of western veratrum alkaloids, and the verazine Alkaloid; Getting from the Dali black false hellebore that produce in Yunnan is 3 kinds of verazine Alkaloids; From the black purple black false hellebore that grows in Taiwan, only get the verazine Alkaloid; From veratrum stenophyllum Diels, get a kind of verazine Alkaloid and stenopbylline A, the significant hypotensive activity of latter's tool.Someone compares deep research to the white hellebore of central Europe and south growth, gets 2 kinds of different steroidal alkaloids of western veratrum alkaloids, 5 kinds of barytine Alkaloids and a kind of veratramin(e) Alkaloid; From U.S. product White hellebore, get 25 kinds of tetrahydroisoquinoline alkaloids, get 4 kinds of solanine Alkaloids and two kinds of verazine Alkaloids recently again.
The Veratrum plant contains the tetrahydroisoquinoline alkaloid of biologically active, studies have shown that total alkaloids has remarkable hypotensive effect, but which kind of monomer component plays main pharmacodynamics and do not appear in the newspapers in the total alkaloids.
Summary of the invention
The objective of the invention is to from Liliaceae (Liliaceae) plant RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.), isolate a steroidal alkaloid veratramine with hypotensive effect, another purpose provides this bonded preparation method, and further purpose provides the application of this compound in the preparation antihypertensive drugs.
The present invention is a raw material with the dry rhizome of Liliaceae (Liliaceae) plant RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.), soak into and the chloroform immersion by dilute alkaline soln, separate the steroidal alkaloid veratramine that obtains a following formula (1) expression, but intact animal and hypertension model animal all there are tangible hypotensive effect and reducing heart rate, and have hypotensive effect mitigation and persistent characteristics.Veratramin(e) has the pharmacologically active similar or close to veratrum alkaloid, and pointing out it may be one of main effective constituent of veratrum alkaloid hypotensive effect.Thereby realized purpose of the present invention.
Veratramin(e) of the present invention is represented by formula (1):
Formula (1)
The veratramin(e) of formula of the present invention (1) expression separates from Liliaceae (Liliaceae) plant RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.) and obtains, and its preparation method may further comprise the steps:
(1) dry rhizome with RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.) plant is a raw material, is ground into coarse particles, puts in the encloses container, soaked into 0.5～2 hour with 0.1%～1% alkaline solution, extraordinarily go into chloroform by material quantity 3～8 again and soak, filter, filtrate continues to be concentrated into the thick paste shape after reclaiming solvent;
(2) the thick paste shape enriched material that obtains of step (1) filters with 1%～10% acid solution dissolving of its 10～30 times of amounts, transfers pH to 8～10, and the refrigerator cold-storage layer was placed 24～48 hours, filtered the collecting precipitation thing;
(3) throw out that step (2) is obtained filters with the chloroform heating for dissolving, and filtrate recovery solvent dissolves to place to separate out with chloroform to closely dried back and freezes the shape thing, drains, and gets powder;
(4) powder that step (3) is obtained is placed with the dissolving of volume ratio 7～10:1 chloroform-methanol, separates out coarse-grain, and coarse-grain is purified, gets above-mentioned formula (1) compound.
Alkaline solution can be aqueous sodium hydroxide solution, potassium hydroxide aqueous solution or ammoniacal liquor described in the step (1), and described chloroform soaks 3～5 times, soaks 1～7 day at every turn; Acid solution can be 1%～5% aqueous tartaric acid solution described in the step (2), 2%～5% sulphuric acid soln or 5%～10% hydrochloric acid soln; Described filtrate is transferred pH to 8～10 with the sodium hydroxide or the potassium hydroxide of 20%～30% ammoniacal liquor or 1%～8%; Coarse-grain purifying described in the step (4) is earlier through silica gel dry chromatography, recrystallization then.
The experiment proved that veratramin(e) of the present invention can be in the application in the treatment hypertension.
But veratramin(e) of the present invention all has tangible hypotensive effect and reducing heart rate to intact animal and hypertension model animal, especially the hypertension model animal there is good action, its hypotensive effect intensity strengthens with the increase of dosage, and hypotensive effect relaxes and is lasting, respiratory rate in addition also can obviously slow down, for instructing clinical application to have actual value, though and positive control drug department Leping has strong and persistent hypotensive effect equally, the phenomenon of accelerating heart rate is arranged.
Embodiment
Following embodiment further specifies of the present invention, but the invention is not restricted to following embodiment.
Embodiment 1: the preparation of the veratramin(e) of above-mentioned formula (1) expression
Black false hellebore is ground into coarse particles (2kg), puts in the encloses container, soaked into 0.5 hour with 0.4% sodium hydroxide (100mL), add 5 times of amounts (about 6.8L) chloroform and soak three times, soaked 2 days at every turn, filter, filtrate is reclaimed solvent, continue to be concentrated into thick paste shape (60g), stir with 20 times of (1200g) 5% aqueous tartaric acid solution and make dissolving, filter, filtrate is transferred pH to 8～9 with 25% ammoniacal liquor, the refrigerator cold-storage layer was placed 24 hours, filtered the collecting precipitation thing.Throw out with the chloroform heating for dissolving, is filtered, and it is closely dried that filtrate is reclaimed solvent, changes with chloroform to be dissolved in the Boiling tube, places to separate out and freeze the shape thing, drains, and gets black false hellebore total alkaloids powder 12g.This powder with chloroform-methanol (volume ratio 9:1) dissolving, is placed, separated out coarse-grain (2g).Coarse-grain (0.2g) earlier through the silica gel dry chromatography (get silica gel 2g, pillar diameter 2cm, highly about 10cm, eluent: volume ratio 8:1 chloroform-methanol), collect elutriant then, evaporate to dryness must white, needle-shaped crystals (0.12g).Determine that by analysis this compound is the compound of formula (1), analytical data is as follows: colourless fine needle crystal, fusing point 214.2-216.5 ℃; EIMS:m/z410[M+H]
+, infer that its molecular formula is C
27H
39NO
2Low field signal δ in the carbon spectrum
C139.5,131.9,142.6,118.7,124.7 and 142.2, prompting has one four substituted benzene ring to exist, other signal δ in low
C141.8,120.5, prompting has the two keys of ring to exist, control reference document (Tezuka Y, Kikuchi T, Zhao W, Chen J, Guo Y.Two new steroidalalkaloids, 20-isoveratramine and verapatuline, from the roots and rhizomes ofVeratrum patulum.J.Nat.Prod.1998,61,1078-1081), approaching with veratramin(e) (veratramine) and the different veratramin(e) of isomer 20-(20-isoveratramine) thereof.The specific rotation of compound ([α]
D 25-55.9 (CHCl
3, c=0.5) consistent with the document veratramin(e) [α]
D 25-60.21 °, c=0.29, MeOH).The detailed nuclear magnetic spectrum data of this compound see Table 1 in addition.
The compound of table 1 formula of the present invention (1)
1H,
13The C nuclear magnetic resonance data
Continuous table 1
Embodiment 2: the compound that embodiment 1 obtains is to the experimental study of the influence of normal cats blood pressure
Get 30 healthy cats, five equilibrium is five groups at random, 6 every group.Laboratory animal is with 5% urethane 1g/kg intraperitoneal injection of anesthesia
[1], to face upward a fixing operation and expose left common carotid artery, the left common carotid artery intubate also is connected on the PT14M2 type pressure transmitter.Be connected in the cat thorax by means of JH-2 type muscular tension transducer sensor and breathe obviously place's recording respiration; Four limbs connect the electrocardio lead, and above signal is by MS-2000 multimedization bio signal record analysis system synchronous recording.Art finish stablize 30 minutes after, survey normal value before the administration, duodenum once gives compound 1.0,0.5, the 0.25mg/kg that embodiment obtains then, respectively as experimental group 1,2,3, the Leping 0.156mg/kg of positive controls department, the blank group is given propylene glycol solution, and volume is 5ml/kg.The systolic pressure (SBP), diastolic pressure (DBP), mean pressure (MP), heart rate (HR) of 15～150min and the variation of breathing before the record administration and after the administration.Forward and backward self difference of administration and change the percentile significance of difference relatively with control group.Compound of the present invention sees Table 2 to the influence of normal cats diastolic pressure, n=6 wherein, X ± SD, * p＜0.05; * p＜0.01; * * p＜0.001; Compound of the present invention sees Table 3 to the influence of normal cats systolic pressure, n=6 wherein, X ± SD, * p＜0.05; * p＜0.01; * * p＜0.001; Compound of the present invention sees Table 4 to the influence of normal cats heart rate, n=6 wherein, X ± SD, * p＜0.05.
The compound of table 2 formula of the present invention (1) is to the influence of normal cats diastolic pressure
The compound of table 3 formula of the present invention (1) is to the influence of normal cats systolic pressure
The compound of table 4 formula of the present invention (1) is to the influence of normal cats heart rate
Embodiment 3: the compound that embodiment 1 obtains is to the influence of SHR spontaneous hypertensive rat blood pressure
Adopt the tail platen press, get 50 of qualified SHR rats, male and female half and half tests preceding 1 week, regularly adopt every day RBP-1 type rat blood pressure instrument to measure caudal artery systolic pressure (SBP), get all interior mediodespidine averages and are worth before as medicine.According to SBP level, body weight five groups of five equilibriums at random, once irritate compound 2.24,1.12,0.56mg/kg that stomach embodiment 1 obtains, respectively as experimental group 1,2,3, the Leping 0.36mg/kg of positive controls department, model group gives distilled water, and volume is 20mL/kg.0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h respectively measure blood pressure once behind medicine, relatively forward and backward self difference of administration and change the percentile significance of difference with control group.Compound of the present invention sees Table 5 to the influence of spontaneous hypertensive rat blood pressure, n=10 wherein, X ± SD, * p＜0.05; * p＜0.01; * * p＜0.001.The compound of formula of the present invention (1) sees Table 6 to the influence of spontaneous hypertensive rat heart rate, n=10 wherein, X ± SD, * p＜0.05; * p＜0.01; * * p＜0.001.
The compound of table 5 formula of the present invention (1) is to the influence of spontaneous hypertensive rat blood pressure
The compound of table 6 formula of the present invention (1) is to the influence of spontaneous hypertensive rat heart rate
Claims (4)
1. the compound of formula (1) expression:
Formula (1)
2. the preparation method of the described compound of claim 1, its feature may further comprise the steps:
(1) dry rhizome with RADIX ET RHIZOMA VERATRI NIGRI (Veratrum nigrum L.) plant is a raw material, is ground into coarse particles, puts in the encloses container, soaked into 0.5～2 hour with 0.1%～1% alkaline solution, extraordinarily go into chloroform by material quantity 3～8 again and soak, filter, filtrate continues to be concentrated into the thick paste shape after reclaiming solvent;
(2) the thick paste shape enriched material that obtains of step (1) filters with 1%～10% acid solution dissolving of its 10～30 times of amounts, and filtrate is transferred pH to 8～10, and the refrigerator cold-storage layer was placed 24～48 hours, filtered the collecting precipitation thing;
(3) throw out that step (2) is obtained filters with the chloroform heating for dissolving, and filtrate recovery solvent dissolves to place to separate out with chloroform to closely dried back and freezes the shape thing, drains, and gets powder;
(4) powder that step (3) is obtained is placed with the dissolving of volume ratio 7～10:1 chloroform-methanol, separates out coarse-grain, and coarse-grain is purified, gets above-mentioned formula (1) compound.
3. preparation method according to claim 2 is characterized in that alkaline solution is aqueous sodium hydroxide solution, potassium hydroxide aqueous solution or ammoniacal liquor described in the step (1), and described chloroform soaks 3～5 times, soaks 1～7 day at every turn; Acid solution is 1%～5% aqueous tartaric acid solution described in the step (2), 2%～5% sulphuric acid soln or 5%～10% hydrochloric acid soln; Described filtrate is transferred pH to 8～10 with the sodium hydroxide or the potassium hydroxide of 20%～30% ammoniacal liquor or 1%～8%; Coarse-grain purifying described in the step (4) is earlier through silica gel dry chromatography, recrystallization then.
4. the application of the described compound of claim 1 in the hypertensive medicine of preparation treatment.
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| CNA200810198639XA CN101362791A (en) | 2008-09-19 | 2008-09-19 | Steroidal alkaloid veratramine, preparation method thereof and antihypertensive application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101565445B (en) * | 2009-06-02 | 2012-05-30 | 中国人民解放军第二军医大学 | Method for preparing high-purity veratramine and jervine |
| CN103520431A (en) * | 2012-07-04 | 2014-01-22 | 江苏天晟药业有限公司 | Preparation method of veratrum alkaloid |
| CN113072607A (en) * | 2021-04-01 | 2021-07-06 | 杭州医学院 | Smo protein-targeted Hedgehog signal pathway inhibitor and preparation method and application thereof |
-
2008
- 2008-09-19 CN CNA200810198639XA patent/CN101362791A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101565445B (en) * | 2009-06-02 | 2012-05-30 | 中国人民解放军第二军医大学 | Method for preparing high-purity veratramine and jervine |
| CN103520431A (en) * | 2012-07-04 | 2014-01-22 | 江苏天晟药业有限公司 | Preparation method of veratrum alkaloid |
| CN113072607A (en) * | 2021-04-01 | 2021-07-06 | 杭州医学院 | Smo protein-targeted Hedgehog signal pathway inhibitor and preparation method and application thereof |
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Open date: 20090211 |