CN102038697A - Anti-anxiety medicament and application thereof - Google Patents
Anti-anxiety medicament and application thereof Download PDFInfo
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- CN102038697A CN102038697A CN2010105292402A CN201010529240A CN102038697A CN 102038697 A CN102038697 A CN 102038697A CN 2010105292402 A CN2010105292402 A CN 2010105292402A CN 201010529240 A CN201010529240 A CN 201010529240A CN 102038697 A CN102038697 A CN 102038697A
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Abstract
The invention provides an anti-anxiety medicament which contains nepodin-8-O-beta-D-glucopyranoside and derivatives thereof and a pharmaceutical carrier or an excipient, and application of the nepodin-8-O-beta-D-glucopyranoside and the derivatives thereof to the preparation of the anti-anxiety medicament and functional foods.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals, (Nepodin-8-O-β-D-glucopyranoside) and derivant thereof be for imitating the pharmaceutical preparation or the functional food of composition preparation, rumicin-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and the application of derivant in anxiolytic drugs and functional food thereof to relate to a kind of rumicin-8-O-β-D-glucopyranoside particularly.
Background technology:
Anxiety neurosis is a kind of general mental maladjustment, brain dysfunction with persistency anxiety, fear, intense strain and vegetative nerve moving obstacle, often the uneasy and body sense of discomfort with the mobility is common clinically, multiple, has a strong impact on patient's quality of life.Along with social development, work rhythm is accelerated, and competition is growing more intense, and the sickness rate of anxiety neurosis presents the trend that rises year by year in recent years.The people that epidemiological study shows nearly 4.1-6.6% in the city can get anxiety neurosis in life at them.Anxiety patient is except having unhappy or painful emotional experience; usually also with chronic pharyngolaryngitis, oral ulcer, irritable bowel syndrome, colitis, chronic gastritis, dizziness, giddy, insomnia, dreaminess; poor memory, bradykinesia, neurasthenia, premature ejaculation, easy catching a cold, hypoimmunity etc.Therefore paying close attention to anxiety neurosis becomes to improve the quality of living and enjoys popular confidence.The antianxiety drugs of clinical practice at present mainly comprises benzodiazepine, selective serotonin reuptake inhibitor, and as fluoxetine, oxidase inhibitor, adrenoceptor blocker, azaperone class etc.Because of anxiety neurosis cause of disease complexity, and these above-mentioned medicines exist such or such problem and defective, therefore research and develop the focus that new antianxiety drugs is world's pharmaceutical industry always.The target spot of being paid close attention in the anxiolytic drugs research and development mainly concentrates on several aspects such as gamma-aminobutyric acid receptor, 5-HT receptor, neurosteroid, cholecystokinin receptor, corticotropin-releasing factor receptor body, histamine H receptor, nmda receptor and cholinergic ion channel.Existing studies show that with these target spots be model find and develop antianxiety drug can the success.Ideal antianxiety drug should be to find the high selectivity part relevant with these anxiety target spots.Animal model antianxity has multiple, mainly is two big class, i.e. conditioned response and UCR experiments but divide from mechanism.Overhead cross labyrinth and light and shade case shuttle back and forth and belong to unconditioned reflex, be based on animal spontaneous, instinct probe into experiment.Because the morbidity of anxiety is closely related with Nervous and Mental Factors such as anxiety, fears, therefore above-mentioned model becomes the classical model of finding anxiolytic drugs, is widely adopted in the research of screening anxiolytic drugs.
Chinese medicine there is no saying of " anxiety neurosis ", but according to the cause of disease and the clinical symptoms of anxiety neurosis, and it should belong to and is " strongly fragrant disease ", " being insomnia ", " palpitation with a distress feeling ", " Bulbus Lilii syndrome ", " hysteria ", " lantern disease " " palpitation with fear " etc.Ancient Chinese medicine doctor pair has also all accumulated comparatively rich experience with the closely-related feelings will of anxiety neurosis treatment of diseases aspect.The traditional Chinese medical science from calm the nerves, arresting convulsion, YANG invigorating, the kidney invigorating, that the equal angles of regulating the flow of vital energy goes to treat anxiety neurosis is effective often clinically.Therefore use for reference Chinese medicine wisdom, it is possible therefrom seeking effective anxiolytic drugs.Rumex is big genus of Polygonaceae; this platymiscium resource of China is very abundant; Radix Rumicis Japonici Rumex japonicus Houtt., curled dock Rumexcrispus L., Rumex patientia Linn. Rumex patientia L., Nepal's Radix rumicis acetosae or Radix Rumicis Crispi Rumex nepalensis Spreng all are called Radix Rumicis, and they contain chemical constituent such as anthraquinone, stilbene and the naphthalene class etc. of general character.Nepal's Radix rumicis acetosae is among the people celebrated with hemostasis and treatment scabies in China, continues to use for a long time.So far, do not have in the prior art rumicin-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and derivant thereof as effective ingredient at the report aspect the anxiety, also this chemical compound and derivant thereof the application report in preparation anxiolytic drugs and functional food not.
Summary of the invention:
The object of the present invention is to provide and a kind ofly contain chemical compound Radix rumicis acetosae element-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and derivant thereof be as the anxiolytic drugs of effective ingredient, and chemical compound Radix rumicis acetosae element-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and the application of derivant in preparation anxiolytic drugs and functional food thereof.
The present invention reaches following purpose of the present invention with following technical scheme:
Anxiolytic drugs, wherein contain the rumicin shown in the formula (I) for the treatment of effective dose-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and derivant and pharmaceutically acceptable carrier or excipient,
R wherein
1Be hydrogen or alkyl or acyl group or glycosyl, R
2Be hydrogen or hydroxyl or methoxyl group or carboxyl, R
3Be halogen, R
4Be acyl group or halogen.
Alkyl is represented methyl, ethyl, propyl group, isopropyl, butyl in rumicin shown in the formula (I)-8-O-β-D-glucopyranoside and the derivant thereof; Acyl group is represented propiono, benzoyl, cinnamyl, Resina Ferulae acyl group, coffee acyl; Glycosyl is represented six carbon pyranoses, five carbon pyranoses, and six carbofuran sugar, five carbofuran sugar, halogen is represented chlorine, fluorine, bromine.
Described anxiolytic drugs, wherein structural formula is the rumicin shown in the formula (II)-8-O-β-D-glucopyranoside,
The application in the preparation anxiolytic drugs of rumicin-8-O-β-D-glucopyranoside and derivant thereof.
The application in preparation anxiety functional food of rumicin-8-O-β-D-glucopyranoside and derivant thereof.
Rumicin of the present invention-8-O-β-D-glucopyranoside (the Nepodin-8-O-β-D-glucopyranoside) and the chemical general formula of derivant thereof are as follows:
R wherein
1Be hydrogen or alkyl (methyl, ethyl, propyl group, isopropyl, butyl); Acyl group (propiono, bytyry, benzoyl, cinnamyl, the Resina Ferulae acyl group, coffee acyl); Hexose (mannose, allose, rhamnose, galactose), pentose (xylose, arabinose).R
2Be hydrogen or hydroxyl or methoxyl group or carboxyl.R
3Be in halogen (chlorine, bromine, fluorine).R
4Be acyl group (acetyl group, propiono, benzoyl, cinnamyl, Resina Ferulae acyl group, coffee acyl) or halogen (chlorine, bromine, fluorine).Be preferably as follows chemical compound in the said derivative:
(Nepodin-8-O-β-D-glucopyranoside) is that extraction separation obtains from the root of Chinese medicine Nepal Radix rumicis acetosae Rumex nepalensis Spreng (Sonchus arvensis L., Radix Rumicis) to chemical compound Radix rumicis acetosae element of the present invention-8-O-β-D-glucopyranoside.Nepal's Radix rumicis acetosae does not have other untoward reaction except that the discharge function that anthraquinone component causes.
The compounds of this invention can directly use or use with the form of pharmaceutical composition during as medicine.The The compounds of this invention that contains 0.1-99% in the pharmaceutical composition.
(method that the Nepodin-8-O-β-D-glucopyranoside) and the pharmaceutical composition of derivant thereof can adopt pharmacy and field of food to generally acknowledge is prepared into various dosage forms to rumicin of the present invention-8-O-β-D-glucopyranoside, as liquid preparation (injection, suspensoid, Emulsion, syrup, tincture etc.), solid preparation (tablet, capsule, dispersible tablet etc.) etc.Medicine of the present invention can be through the number of ways administration, as oral, mucosa, injection etc.
Compared with prior art, the present invention possesses following excellent beneficial effect:
Anxiety neurosis is a kind of unhappiness and painful emotional experience, often follows many other symptoms, therefore has a strong impact on quality of life, but because the cause of disease complexity of anxiety neurosis does not have ideal adjusting medicine on the market.Anxiety neurosis also is a kind of Social disease, and modern society's rhythm and pressure impel anxiety patient to rise, and is same because it belongs to social diseases related, therefore it arranged from ancient times.From traditional medicine knowledge and wisdom, may find the efficient medicine of relevant low toxicity.The wisdom that it is considered herein that successive dynasties sage of the past accumulation is of great use, and therefore the present invention for a long time acts on the oriented active screening from traditional medical theory and experience, has obtained many successes, and the present invention is the oriented active results of screening equally.Nepal Radix rumicis acetosae Rumexnepalensis Spreng belongs to the root of Rumex gmelini Turcz Nepal Radix rumicis acetosae, is a kind of Radix Rumicis.Nepal's Radix rumicis acetosae is used to alleviate psychentonia and Mental Subnormality at Himalaya and India area; Nmda receptor is an important screening model of anxiety neurosis; Based on this, the present invention screens efficiently and finds that Nepal's Radix rumicis acetosae root extract has nmda receptor antagonistic activity preferably, continue to follow the tracks of chemical compound Radix rumicis acetosae element-8-O-β-D-glucopyranoside of being separated to a nmda receptor antagonistic activity (Nepodin-8-O-β-D-glucopyranoside), and content is abundant, in view of the traditional drugs experience, discover that through the animal pharmacodynamics this native compound has significant angst resistance effect.The present invention has carried out anxiety research to its extract and position.The animal pharmacodynamics studies have shown that Nepal's Radix rumicis acetosae has clear and definite drug effect.Simultaneously its extraction position is comprised that petroleum ether, ethyl acetate, n-butanol extraction position carried out nmda receptor antagonistic activity screening, find that the n-butanol portion activity is best.The Chemical Decomposition of system and nmda receptor screening active ingredients find that the abundant chemical compound of a content presents significant anxiety activity on animal model, because the mechanism of action of this chemical compound is relevant with nmda receptor 2A hypotype, and nmda receptor is an important target spot of screening antianxiety drugs, so the anxiety drug effect effect of this chemical compound is clear and definite mechanism of action to be arranged as supporting.
Description of drawings:
Fig. 1 rumicin-8-O-β-D-glucopyranoside mouse peritoneal injection elevated plus-maze test;
Fig. 2 rumicin-8-O-β-D-glucopyranoside mouse peritoneal injection elevated plus-maze test;
Fig. 3 rumicin-8-O-β-experiment of D-glucopyranoside different way of administration relatively;
Fig. 4 rumicin-8-O-β-D-glucopyranoside mouse stomach elevated plus-maze test;
The experiment of shuttling back and forth of Fig. 5 rumicin-8-O-β D-glucopyranoside mice light and shade case.
The specific embodiment:
Below in conjunction with accompanying drawing, further specify flesh and blood of the present invention with embodiments of the invention, but do not limit to the present invention with this.
Embodiment 1:
Rumicin-8-O-β-D-glucopyranoside (extraction separation of Nepodin-8-O-β-D-glucopyranoside):
Adopt the root 30kg of Polygonaceae Rumex Nepal Radix rumicis acetosae Rumex nepalensis, dry, pulverize, with 95% alcohol reflux 3 times, 240kg ethanol at every turn, 3 extraction times were respectively 3 hours, 2 hours and 2 hours.The merge extractive liquid, decompression and solvent recovery is to there not being the alcohol flavor, water liquid extracts 2 times with the ethyl acetate equal-volume, go up D101 macroporous resin (10kg) post behind the residue water layer decompression and solvent recovery, difference water 75L, 30% ethanol 18L, 45% ethanol 30L, 50% ethanol 27L and 90% ethanol 18L eluting, with rumicin-8-O-β-D-glucopyranoside is contrast, and thin layer detects and to show that rumicin-8-O-β-D-glucopyranoside is can eluting complete in 45-50% ethanol elution part.Merge 45-50% ethanol elution part, sample concentration is to the extractum 85g that does.Use silica gel mixed sample behind the dry extract dissolve with methanol, through 200-300 order silica gel (600g), the chloroform-methanol gradient elution (15: 1,2300mL; 12: 1,960mL; 10: 1,4000mL; 8: 1,4000mL), every 500ml was first-class part, with rumicin-8-O-β-D-glucopyranoside is contrast, merge 11-16 stream part of containing rumicin-8-O-β-D-glucopyranoside, sample mainly concentrates on 10: 1-8: 1 chloroform-methanol eluting position, decompression and solvent recovery is to doing.The heavy 20g of this part, contain rumicin-8-O-β-D-glucopyranoside, it passes through MCI gel CHP 20P (700g) post again, water with 2 times of bed volumes, 30%, 35%, 40% methanol-eluted fractions, merge 35% methanol-eluted fractions part, be evaporated to dried extractum 14g, it is further through vacuum silica gel column chromatography (10-40 μ M, 200g), with 12: 1 eluting of chloroform-methanol, every 300mL is first-class part, is contrast with rumicin-8-O-β-D-glucopyranoside, merge 4-5 stream part of containing rumicin-8-O-β-D-glucopyranoside, concentrating under reduced pressure is dry must pure product 12g.
Structure determination: optically-active is measured with Horiba SEPA-300 polarimeter; Ultraviolet spectra Shimadzu UV-2401PC spectrophotometric determination; Infrared spectrum Tensor 27 spectrophotometer, pressing potassium bromide troche; Electrospray Mass Spectrometry API QSTAR Pulsar 1 spectrophotometer; Nuclear magnetic resoance spectrum is measured by Bruker AM-400 NMR spectrometer with superconducting magnet, and TMS is interior mark, and chemical shift δ represents that with ppm coupling constant J represents with Hz, CD
3OD makes test solvent.
Rumicin-8-O-β-D-glucopyranoside structured data
Chinese name: rumicin-8-O-β-D-glucopyranoside
English name: Nepodin-8-O-β-D-glucopyranoside
Structural formula: as follows.
Molecular formula: C
19H
22O
8
Molecular weight: 378
Character: white solid powder; Spray anisaldehyde reagent shows green on the lamellae.
[α]
D 17:-119.8 (c 0.52, methanol)
UV(MeOH)λ
max(logε)：335(3.71)，300(3.72)，260(sh)，225(4.67)。
IR(KBr)：3387，3300，2963，2925，2888，2856，1670，1634，1609，1580，1493，1470，1443，1355，1264，1231，1087，1036，1020，933，889，853cm
-1。
ESI-MS (anion) m/z:413[M+Cl]
-377[M-H]
-
1H?NMR(CD
3OD，400MHz)δ：7.40(1H，dd，J＝8.0Hz，7.6Hz，H-6)，7.37(1H，br?d，J＝8.0Hz，H-5)，7.30(1H，br?d，J＝7.6Hz，H-7)，7.11(1H，s，H-4)，2.58(3H，s，COCH3)，2.28(3H，s，Me-3)，5.09(1H，d，J＝7.6Hz，H-1’)，3.74(1H，m，H-2’)，3.56(1H，m，H-3’)，3.33(1H，m，H-4’)，3.49(1H，m，H-5’)，3.72(1H，m，Ha-6’)，3.95(1H，m，Hb-6’)。
13C?NMR(CD
3OD，100MHz)δ：151.4(C-1)，124.7(C-2)，133.2(C-3)，119.6(C-4)，122.5(C-5)，127.2(C-6)，110.5(C-7)，154.7(C-8)，113.5(C-9)，136.7(C-10)，207.0(2-
COCH
3)，31.0(2-CO
CH
3)，18.5(3-CH
3)，102.9(C-1’)，73.6(C-2’)，77.4(C-3’)，69.9(C-4’)，76.8(C-5’)，61.1(C-6’)。
Embodiment 2:
Rumicin-8-O-β-D-(6 '-O-trans-crotonyl) glucopyranoside (preparation of Nepodin-8-O-β-D-(6 '-O-trans-crotonoyl) glucopyranoside):
Experiment is picked up from the Kunming, Yunnan Province with Nepal's Radix rumicis acetosae, is the dry root of polygonaceae plant Nepal Radix rumicis acetosae Rumex neaplensis Spreng..Sample 15kg pulverizes the back with 8 times of volumes, 95% alcohol reflux 3 times, each 2 hours.The extracting solution decompression recycling ethanol obtains fluid extract, adds 4 times of water gaging suspendibles, respectively extracts 3 times with equivalent petroleum ether, ethyl acetate successively.Combined ethyl acetate extracting solution, concentrating under reduced pressure get extractum 488g.(the 200-300 order 5kg), is used chloroform-methanol gradient elution (100: 0 to dry method upper prop behind the silica gel mixed sample, 98: 2,96: 4,94: 6,92: 8,90: 10,85: 15,80: 20,75: 25,70: 30), each gradient 5000mL, every 1000mL is first-class part, obtains 7 eluting parts (Fr.1-7).(6-7 flows part to Fr.3; 26g) through silicagel column (200-300 order; 300g) chromatography; with chloroform-acetone gradient elution (4: 1 → 1: 1); each gradient 1000mL, every 500mL are first-class part, merge 3-4 stream part; concentrating under reduced pressure; pass through silica gel column chromatography (10-40 μ M, 100g, chloroform-methanol 3: 1 again; 2000mL); every 200mL is first-class part, merges 4-5 stream part, passes through Sephadex LH-20 column chromatography again behind the recovery solvent; methanol-eluted fractions obtains chemical compound Radix rumicis acetosae element-8-O-β-D-(6 '-O-trans-crotonyl) glucopyranoside (31mg).
Structured data: structure is as follows:
The white solid powder; Spray anisaldehyde reagent shows green on the lamellae; Molecular formula is C
23H
26O
9Mp 67-68 ℃; [α]
D 21.6-45.14 ° (c 0.96, MeOH); UV (CHCl
3) λ
Max(log ε) nm:334 (3.54), 299 (3.57); IR v
Max(KBr) cm
-1: 3414 (OH), 1721 (C=O), 1698 (C=O), 1631 (C-C), 1578 (C-C), 1078 (C-O);
1HNMR (CDCl
3, 500MHz) and
13C NMR (CDCl
3, 125MHz) see the following form; FABMS (negative) m/z:445[M-H]
-, 215; HRFABMS (negative) m/z:445.1506[M-H]
-(calcd.for C
23H
25O
9, 445.1498).
The nuclear magnetic resonance data of table 1 rumicin-8-O-β-D-(6 '-O-trans-crotonyl) glucopyranoside
Embodiment 3:
Torachrysone-8-O-β-D-(preparation of 6 '-O-acetyl) glucopyrancoside:
Experiment is picked up from the Kunming, Yunnan Province with Nepal's Radix rumicis acetosae, is the dry root of polygonaceae plant Nepal Radix rumicis acetosae Rumex neaplensis Spreng..Sample 15kg pulverizes the back with 8 times of volumes, 95% alcohol reflux 3 times, each 2 hours.The extracting solution decompression recycling ethanol obtains fluid extract, adds 4 times of water gaging suspendibles, respectively extracts 3 times with equivalent petroleum ether, ethyl acetate successively.Combined ethyl acetate extracting solution, concentrating under reduced pressure get extractum 488g.Dry method upper prop behind the silica gel mixed sample (the 200-300 order, 5kg), usefulness chloroform-methanol gradient elution (100: 0,98: 2,96: 4,94: 6,92: 8,90: 10,85: 15,80: 20,75: 25,70: 30), every 1000mL is first-class part, obtains 7 eluting parts (Fr.1-7).(8-10 flows part to Fr.4,22g) through silicagel column (200-300 order, 250g) chromatography, with chloroform-acetone gradient elution (30: 1) eluting, every 300mL is first-class part, part merging of 6-9 stream through MCI gel CHP 20P column chromatography (65% methanol-eluted fractions) and Sephadex LH-20 column chromatography (methanol-eluted fractions), gets chemical compound Torachrysone-8-O-β-D-(6 '-O-acetyl) glucopyrancoside (32mg).
Structured data: structure is as follows.
The white solid powder; Spray anisaldehyde reagent shows green on the lamellae; Molecular formula is C
22H
26O
10Mp 151-153 ℃; [α]
D 22.1-75.60 ° (c0.97, MeOH); UV (CHCl
3) λ
Max(log ε) nm:323 (3.62), 262 (4.18); IR v
Max(KBr) cm
-1: 3422 (OH), 1734 (C=O), 1627 (C-C), 1585 (C-C), 1077 (C-O);
1HNMR (CDCl
3, 400MHz) and
13C NMR (CDCl
3, 100MHz) see Table 2;
FABMS(negative)m/z：449[M-H]
-，245；HRFABMS(negative)m/z：449.1441[M-H]
-(calcd.for?C
22H
25O
10，449.1447)。
Table 2Torachrysone-8-O-β-D-(nuclear magnetic resonance data of 6 '-O-acetyl) glucopyrancoside
Embodiment 4:
The preparation of rumicin-8-O-β-D-(6 '-O-glucopyanosyl base) glucopyranoside (Orientaloside):
Experiment is picked up from the Kunming, Yunnan Province with Nepal's Radix rumicis acetosae, is the dry root of polygonaceae plant Nepal Radix rumicis acetosae Rumex neaplensis Spreng..Sample 15kg pulverizes the back with 8 times of volumes, 95% alcohol reflux 3 times, each 2 hours.The extracting solution decompression recycling ethanol obtains fluid extract, adds 4 times of water gaging suspendibles, respectively extracts 3 times with equivalent petroleum ether, ethyl acetate, n-butyl alcohol successively.Merge butanol extraction liquid, concentrating under reduced pressure gets extractum 300g.Dry method upper prop behind the silica gel mixed sample (the 200-300 order, 4kg), usefulness chloroform-methanol gradient elution (15: 1,12: 1,9: 1,6: 1,4: 1,2: 1), every gradient 4000mL, every 1000mL are first-class part, obtain 4 streams part (a Fr A-D).Fr.C (60g) is through silica gel column chromatography (200-300 order, 800g, chloroform-methanol 7: 1), every 500mL is first-class part, part merging of 6-7 stream, pass through Sephadex LH-20 (methanol: water then, 80: 20 eluting), every 50mL is first-class part, part merging of 10-13 stream, after silicagel column (200-300 order, 60g, chloroform: methanol, 12: 1,9: 1,7: 1) eluting, each gradient is 300mL, every 20mL is first-class part, part merging of 28-36 stream, the concentrating under reduced pressure drying obtains Orientaloside (180mg).
Structured data: structure is as follows.
White powder; Molecular formula is C
25H
32O
13 1H NMR (C
5D
5N, 400MHz) δ: 7.20 (1H, s, H-4), 7.47 (1H, m, H-5), 7.50 (1H, m, H-6), 7.57 (1H, m, H-7), 2.41 (3H, s, 3-CH
3), 2.71 (3H, s, 2-COCH
3), 5.59 (1H, d, J=7.5Hz, H-1 '), 5.13 (1H, d, J=6.9Hz, H-1 ").
13C?NMR(C
5D
5N，100MHz)δ：150.1(C-1)，126.1(C-2)，137.1(C-3)，120.4(C-4)，123.4(C-5)，127.6(C-6)，112.4(C-7)，155.8(C-8)，114.6(C-9)，134.0(C-10)，205.2(2-
COCH
3)，32.4(2-CO
CH
3)，20.0(3-
CH
3)，104.6(glc-1’)，74.7(glc-2’)，78.4(glc-3’)，71.4(glc-4’)，78.5(glc-5’)，70.1(glc-6’)，105.6(glc-1”)，75.4(glc-2”)，78.5(glc-3”)，71.8(glc-4”)，78.5(glc-5”)，62.7(glc-6”)。
Embodiment 5:
The preparation of 6-hydroxyl rumicin-8-O-β-D-glucopyranoside:
Experiment is picked up from the Kunming, Yunnan Province with Nepal's Radix rumicis acetosae, is the dry root of polygonaceae plant Nepal Radix rumicis acetosae Rumex neaplensis Spreng..Sample 15kg pulverizes the back with 8 times of volumes, 95% alcohol reflux 3 times, each 2 hours.The extracting solution decompression recycling ethanol obtains fluid extract, adds 4 times of water gaging suspendibles, respectively extracts 3 times with equivalent petroleum ether, ethyl acetate successively.Combined ethyl acetate extracting solution, concentrating under reduced pressure get extractum 488g.Dry method upper prop behind the silica gel mixed sample (the 200-300 order, 5kg), usefulness chloroform-methanol gradient elution (100: 0,98: 2,96: 4,94: 6,92: 8,90: 10,85: 15,80: 20,75: 25,70: 30), every 1000mL is first-class part, obtains 7 eluting parts (Fr.1-7).Fr.7 (17-19 flows part, 23g) through silica gel column chromatography (the 200-300 order, 250g), with chloroform-methanol gradient elution (15: 1,12: 1,9: 1,7: 1), each gradient 1000mL, every 400mL is first-class part, and Sephadex LH-20 column chromatography is passed through in part merging of 6-8 stream again, methanol-eluted fractions obtains chemical compound 6-hydroxyl rumicin-8-O-β-D-glucopyranoside (38mg).
Structured data: structure is as follows.
White powder; Spray anisaldehyde reagent shows green on the lamellae; Molecular formula is C
19H
22O
9 1HNMR (DMSO-d
6, 400MHz) δ: 6.96 (1H, d, J=2.1Hz, H-5), 6.90 (1H, s, H-4), 6.68 (1H, d, J=2.1Hz, H-7), 5.08 (1H, d, J=7.4Hz, H-1 '), 3.30～3.99 (6H, m, H-2 ', 3 ', 4 ', 5 ', 6 '), 2.58 (3H, s, 2-COC
H 3), 2.27 (3H, s, 3-C
H 3).
13C?NMR(DMSO-d
6，100MHz)δ：
13C?NMR(CD
3OD，100MHz)δ：154.41(C-1)，123.1(C-2)，135.3(C-3)，119.7(C-4)，105.4(C-5)，158.2(C-6)，104.5(C-7)，157.4(C-8)，109.6(C-9)，139.5(C-10)，208.2(2-
COCH
3)，32.6(2-CO
CH
3)，20.3(3-CH
3)，104.3(C-1’)，74.9(C-2’)，78.8(C-3’)，71.2(C-4’)，78.1(C-5’)，62.4(C-6’)。
FABMS(negative)m/z：393[M-H]
-，231[M-H-glc]
-。
Embodiment 6:
Semen Cassiae ketone-8-O-β-D-glucopyranoside (preparation of Torachrysone-8-O-β-D-glucopyrancoside):
Experiment is picked up from the Kunming, Yunnan Province with Nepal's Radix rumicis acetosae, is the dry root of polygonaceae plant Nepal Radix rumicis acetosae Rumex neaplensis Spreng..Sample 15kg pulverizes the back with 8 times of volumes, 95% alcohol reflux 3 times, each 2 hours.The extracting solution decompression recycling ethanol obtains fluid extract, adds 4 times of water gaging suspendibles, respectively extracts 3 times with equivalent petroleum ether, ethyl acetate successively.Combined ethyl acetate extracting solution, concentrating under reduced pressure get extractum 488g.Dry method upper prop behind the silica gel mixed sample (the 200-300 order, 5kg), usefulness chloroform-methanol gradient elution (100: 0,98: 2,96: 4,94: 6,92: 8,90: 10,85: 15,80: 20,75: 25,70: 30), every 1000mL is first-class part, obtains 7 eluting parts (Fr.1-7).(14-16 flows part to Fr.6,28g) through silica gel column chromatography (the 200-300 order, 350g), with chloroform-methanol gradient elution (15: 1,12: 1,9: 1), each gradient 1000mL solvent elution, every 300mL are first-class part, part merging of 5-7 stream, pass through Sephadex LH-20 column chromatography again, methanol-eluted fractions obtains chemical compound Semen Cassiae ketone-8-O-β-D-glucopyranoside (136mg).
Structured data: white powder; Spray anisaldehyde reagent shows green on the lamellae; Molecular formula is C
20H
24O
9 1H NMR (DMSO-d
6, 400MHz) δ: 7.00 (1H, s, H-4), 6.98 (1H, d, J=1.6Hz, H-5), 6.79 (1H, d, J=1.6Hz, H-7), 5.09 (1H, d, J=6.2Hz, H-1 '), 3.14-3.80 (6H, m, H-2 ', 3 ', 4 ', 5 ', 6 '), 3.85 (3H, s, 6-OC
H 3), 2.56 (3H, s, 2-COC
H 3), 2.27 (3H, s, 3-C
H 3).
13C?NMR(DMSO-d
6，100MHz)δ：151.5(C-1)，123.3(C-2)，133.8(C-3)，118.9(C-4)，102.8(C-5)，158.5(C-6)，101.3(C-7)，155.5(C-8)，108.7(C-9)，137.0(C-10)，204.6(2-
COCH
3)，32.2(2-CO
CH
3)，19.5(3-
CH
3)，55.4(6-OCH
3)，103.2(C-1’)，73.4(C-2’)，77.9(C-3’)，69.9(C-4’)，76.2(C-5’)，60.8(C-6’)。
Embodiment 7:
(Nepodin-8-O-β-D-glucopyranoside) waits chemical compound to the rumicin that embodiment 1-6 makes-8-O-β-D-glucopyranoside, is 1 in its ratio with excipient respectively: 5-1: 10 ratio adding excipient, pelletizing press sheet.
Embodiment 8:
(Nepodin-8-O-β-D-glucopyranoside) waits chemical compound to the Nepodin-8-O-β that embodiment 1-6 makes-D-glucopyranosid rumicin-8-O-β-D-glucopyranoside, ratio in itself and excipient is 1 respectively: 1-1: 10 ratio adds excipient, makes capsule according to conventional method.
Embodiment 9:
(Nepodin-8-O-β-D-glucopyranoside) wait chemical compound makes oral liquid according to conventional method respectively to the rumicin that embodiment 1-6 makes-8-O-β-D-glucopyranoside.
Embodiment 10:
Rumicin-8-O-β-D-the glucopyranoside that makes by embodiment 1-6 (Nepodin-8-O-β-D-glucopyranoside) wait chemical compound adds the injection water according to conventional method respectively, fine straining, and injection is made in the embedding sterilization.
Embodiment 11:
Get rumicin-8-O-β-D-glucopyranoside that 1 part of embodiment 1-6 makes (Nepodin-8-O-β-D-glucopyranoside) or other chemical compounds, it with 20 parts of degree of polymerization respectively 300 vinylacetate resin, 2 parts of butyl phthalate, 3 parts of carnauba wax and 20 portions of maltose mixed 3 minutes in 50 ℃ in pinching machine, add 50 portions of Saccharum Sinensis Roxb. again, 1 portion of Herba Menthae, chewing gum is extruded in mixing even back from extruder under 50 ℃ of constant temperature, cut into specific thickness, as functional food.
In order to understand the present invention better, (Nepodin-8-O-β-D-glucopyranoside) and derivant thereof describe as concrete test example with the pharmacological action of the pharmaceutical composition that pharmaceutic adjuvant or excipient are formed, but do not limit the present invention with this below in conjunction with rumicin of the present invention-8-O-β-D-glucopyranoside.
Test example 1.:
Rumicin-8-O-β-D-glucopyranoside (the overhead cross maze test of anxiety activity-mice of Nepodin-8-O-β-D-glucopyranoside) (numbering NBSM-15):
(1) experimental principle: rodent has the characteristic of probing into new environment, but detests high light and open ground.People such as Pellow in 1985 according to this characteristics design overhead cross labyrinth, and paint black.The relative arm (closed arms) that closes of splitting arm (open arms) and two 50cm * 10cm * 40cm mutually that it comprises two 50cm * 10cm closes arm top and opens wide.There is the open portion of one 10cm * 10cm in labyrinth central authorities, and the labyrinth is 50cm overhead, the fear when entering out arm to increase animal.The arm inquiry activity is opened in the antianxiety drug increase, and it is then opposite to cause the anxiety agent.Overhead cross labyrinth is the classical model of screening antianxiety drug.
(2) experimental technique: mice is weighed every day, strokes 1 minute, for three days on end.By body weight random packet, normal group, medicine group and positive controls, normal gastric infusion, once a day, for three days on end, the administration group is established basic, normal, high 3 dosage, give each given the test agent respectively, diazepam is as positive control drug (4mg/kg), and normal group is given and waited the dosage normal saline.After the last administration 30 minutes, mice is placed labyrinth open portion of central authorities, head is towards closing arm.Start shooting and monitoring system, write down mice in 5 minutes and enter out arm and close the number of times of arm and in time of two arms stop.(turnover arm standard should polarize, and all goes into arm or two fore paws with extremity and goes out arm and be as the criterion).Number of times and time that the calculating mice enters out arm account for the percentage ratio of total degree (two arm number of times sums) and total time (in two arm holdup time sums) respectively.With this index as the evaluation anxiety.After administering mode was changed into lumbar injection, the repeated experiments under different way of administration and the various dose the results are shown in down, and wherein the dosage of Fig. 1-4 correspondence is consistent with the dosage among the table 3-6 respectively.
(3) experimental result: open the arm number of times and open the arm holdup time and account for total degree (two arm number of times sums) and the percentage ratio of total time (in two arm holdup time sums) respectively as showing shown in the 3-6.
Table 3 rumicin-8-O-β-D-glucopyranoside mouse peritoneal injection elevated plus-maze test (X ± S)
*P＜0.01,
*P＜0.05vs normal group
Table 4 rumicin-8-O-β-D-glucopyranoside mouse peritoneal injection elevated plus-maze test (X ± S)
*P＜0.01,
*P＜0.05vs normal group
Table 5 rumicin-8-O-β-experiment of D-glucopyranoside different way of administration relatively
*P＜0.01,
*P＜0.05vs normal group
Table 6 rumicin-8-O-β-D-glucopyranoside mouse stomach elevated plus-maze test (X ± S)
*P＜0.01,
*P＜0.05vs normal group
From table 3-6 and Fig. 1-4 various dose, different modes of administration repeatedly more as can be seen, the overhead cross of medicine of the present invention labyrinth anxiety drug effect: (1) its animal (mice) onset scope is at 10-40mg/kg, as a result good reproducibility; (2) lumbar injection and irritate the onset dosage basically identical of two kinds of different modes of administration of stomach shows injection and oral all effective, and its bioavailability etc. is not subjected to the influence of route of administration.
Test example 2:
Rumicin-8-O-β-D-glucopyranoside (test of shuttling back and forth of anxiety activity-mice light and shade case of Nepodin-8-O-β-D-glucopyranoside) (numbering NBSM-15):
(1) experimental principle: in the light and shade case, mice or rat are liked in the camera bellows activity, but the habit of probing into of animal impels it to attempt to probe into camera-lucida.Yet the light stimulation of camera-lucida suppresses the inquiry activity of animal at camera-lucida again.Antianxiety drugs can be removed this inhibitory action.
(2) experimental technique: (45cm * 27cm * 27cm) inside is divided into camera-lucida and camera bellows to the light and shade case, and wherein camera-lucida and camera bellows respectively account for 1/2, and add a cover at the top, and the centre has a dividing plate separately, and the square opening door opening that a 7.5cm * 7.5cm is opened in the bottom of dividing plate passes for animal.Painted white in the camera-lucida, the top is by the incandescent lamp bulb illumination of a 60W; Painted black in the camera bellows, top sustained height have the red bulb illumination of a 25W.Animal grouping and gastric infusion are all with the elevated plus-maze test method, and 30min is placed on camera-lucida central authorities after the administration, wear the case number of times in the record 5min and respectively in holdup time of camera-lucida.
(3) experimental result: camera-lucida time of staying percentage ratio and light and shade case shuttle back and forth number of times shown in table 7 and figure.
Table 7 rumicin-8-O-β-D-glucopyranoside mouse stomach light and shade case experiment (X ± S) that shuttles back and forth
Test example 3:
The acute toxicity testing of rumicin-8-O-β-D-glucopyranoside:
(1) experimental technique: the onset dosage range of determining rumicin-8-O-β-D-glucopyranoside substantially according to above-mentioned experiment is between 10-40mg/kg, and the once abdominal cavity injection administration is adopted in therefore anxious poison experiment.The Kunming male mice is adopted in experiment, and in 6 ages in week, 18-22g is provided by unming Medical College.The animal grouping according to dosage is divided into 50mg/kg, 100mg/kg, 200mg/kg, 400mg/kg, 800mg/kg and normal control group (solvent).Take by weighing quantitative sample and in mortar, add tween 80, grind evenly by same direction, add then that an amount of normal saline fully grinds, sonic oscillation, treat that adding normal saline behind the homodisperse is settled to the maximum dose level desired concn, all the other concentration are prepared successively by coubling dilution.Press the volume lumbar injection of 0.2ml/10g, observe mice 14d, and claim food to weigh, dead in the 14d end, each is organized sample drawn and does the pathology inspection.
(2) experimental result: all are normal for normal group and each dosage group mice hair color, the colour of skin, activity, mental status, body weight change etc., and appetite slightly descends after removing administration in first day, recovers rapidly afterwards.Pathology section examination liver, the heart, spleen, lung, five main organs of kidney show no obvious abnormalities.
Above-mentioned experimental result shows that rumicin-(Nepodin-8-O-β-D-glucopyranoside) have significant angst resistance effect can be used for the treatment of anxiety neurosis to 8-O-β-D-glucopyranoside to The compounds of this invention.
Claims (5)
1. anxiolytic drugs, wherein contain the rumicin shown in the formula (I) for the treatment of effective dose-8-O-β-D-glucopyranoside (Nepodin-8-O-β-D-glucopyranoside) and derivant and pharmaceutically acceptable carrier or excipient,
R wherein
1Be hydrogen or alkyl or acyl group or glycosyl, R
2Be hydrogen or hydroxyl or methoxyl group or carboxyl, R
3Be halogen, R
4Be acyl group or halogen.
2. anxiolytic drugs as claimed in claim 1, alkyl is represented methyl, ethyl, propyl group, isopropyl, butyl in the rumicin shown in its Chinese style (I)-8-O-β-D-glucopyranoside and the derivant thereof; Acyl group is represented propiono, benzoyl, cinnamyl, Resina Ferulae acyl group, coffee acyl; Glycosyl is represented six carbon pyranoses, five carbon pyranoses, and six carbofuran sugar, five carbofuran sugar, halogen is represented chlorine, fluorine, bromine.
3. as claim 1 and 2 described anxiolytic drugs, wherein structural formula is the rumicin shown in the formula (II)-8-O-β-D-glucopyranoside,
4. rumicin-8-O-β-D-the glucopyranoside of the described anxiolytic drugs treatment of claim 1-3 effective dose and the application of derivant in the preparation anxiolytic drugs thereof.
5. rumicin-8-O-β-D-the glucopyranoside of the described anxiolytic drugs treatment of claim 1-3 effective dose and derivant thereof the application in preparation anxiety functional food.
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| CN104188991A (en) * | 2014-09-17 | 2014-12-10 | 蒋冠 | Medicinal composition for inhibiting proliferation of malignant melanoma cells |
| CN105942517A (en) * | 2016-07-16 | 2016-09-21 | 惠安县科联农业科技有限公司 | Anxiety-improving health-care food and preparing method thereof |
| CN106214689A (en) * | 2016-08-25 | 2016-12-14 | 中国科学院昆明植物研究所 | The application in preparing antidepressant drug of the rumicin 8 O β D glucopyranoside |
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| CN101461845A (en) * | 2009-01-12 | 2009-06-24 | 河南大学 | Rumex nepalensis Spreng. extract as well as preparation method and use thereof |
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| 《世界科学技术-中医药现代化》 20080531 张广庆等 酸模属植物的化学成分与药理活性研究进展 86-93 1-5 第10卷, 第5期 2 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104188991A (en) * | 2014-09-17 | 2014-12-10 | 蒋冠 | Medicinal composition for inhibiting proliferation of malignant melanoma cells |
| CN104188991B (en) * | 2014-09-17 | 2016-05-25 | 徐州医学院附属医院 | A kind of pharmaceutical composition of check melanin tumor cell proliferation |
| CN105942517A (en) * | 2016-07-16 | 2016-09-21 | 惠安县科联农业科技有限公司 | Anxiety-improving health-care food and preparing method thereof |
| CN106214689A (en) * | 2016-08-25 | 2016-12-14 | 中国科学院昆明植物研究所 | The application in preparing antidepressant drug of the rumicin 8 O β D glucopyranoside |
| CN106214689B (en) * | 2016-08-25 | 2019-10-29 | 中国科学院昆明植物研究所 | Application of the rumicin -8-O- β-D- glucopyranoside in preparation antidepressant |
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Application publication date: 20110504 Assignee: Beijing Zhongke Wenqing Technology Development Co.,Ltd. Assignor: KUNMING INSTITUTE OF BOTANY, CHINESE ACADEMY OF SCIENCES Contract record no.: X2022530000002 Denomination of invention: Anti anxiety drugs and their application Granted publication date: 20120606 License type: Common License Record date: 20220609 |