CN102775394B - A kind of amides and its preparation method and application - Google Patents

A kind of amides and its preparation method and application Download PDF

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CN102775394B
CN102775394B CN201110123076.XA CN201110123076A CN102775394B CN 102775394 B CN102775394 B CN 102775394B CN 201110123076 A CN201110123076 A CN 201110123076A CN 102775394 B CN102775394 B CN 102775394B
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medicinal extract
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CN102775394A (en
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靳元鹏
罗学军
马晓慧
颜璐璐
轧霁
韩民
周水平
张兰兰
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Tasly Pharmaceutical Group Co Ltd
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Abstract

The present invention relates to a kind of amides and its preparation method and application, specifically, the present invention relates to compound, their preparation method and the drug regimen containing them with formula (I) structure, and the application in preparation treatment and prevention mental disorder medicine, wherein, (C 2-C 3) nat least containing a carbon-carbon single bond and a carbon-carbon double bond, and n is 8.

Description

A kind of amides and its preparation method and application
Technical field
The present invention relates to Chinese materia medica field, specifically, the present invention relates to compound, their preparation method and the drug regimen containing them with formula (I) structure, and the application in preparation treatment and prevention mental disorder medicine.
Background technology
A kind of mental disorder that dysthymia disorders is is cardinal symptom with remarkable and lasting emotional handicap, based on depressed, lose interest, disheartened, the symptoms such as, appetite stimulator too low with psychomotor agitation or sluggishness, self-assessment and insomnia.According to " World Health Report in 2002 " that the World Health Organization delivers, dysthymia disorders has become the fourth-largest illness in the world at present, may become be only second to cardiopathic second largest disease to the year two thousand twenty dysthymia disorders.
At present, the antidepressant drug applied clinically is the serotonin reuptake inhibitor such as fluoxetine, paroxetine and Sertraline mainly, but because depression mechanism is complicated, induced factor is more, medicine for a certain single link is often difficult to obtain satisfactory effect, and synthesis thymoleptic exist that narrow, the side effect of antidepressant spectrum is large, medicine valency is high mostly and drug withdrawal such as easily to recur at the defect.Therefore, more and more focus on both at home and abroad finding activated lead compound in the research and development of thymoleptic from natural product, find new antidepressant drug by structural modification.
Chinese patent CN200410025493.0 discloses laetispicine in great Ye Betel and suppresses the application in central nervous system monoamine transmitters reuptake relevant pharmaceutical composition in preparation treatment.US Patent No. 6858648 also discloses laetispicine and the application of homologue in the mental disorder such as antidepressant thereof.
The present invention extracts a kind of new compound from great Ye Betel, and finds that it has excellent pharmacologically active and extremely low side effect.
Summary of the invention
The invention provides the compound or pharmaceutically acceptable salt thereof that one has formula (I) structure:
Wherein, (C 2-C 3) nat least containing a carbon-carbon single bond and a carbon-carbon double bond, and n is 8.
Formula (I) compound or pharmaceutically acceptable salt thereof, comprises formula (II) compound and formula (III) compound:
1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyl] Pyrrolidine
1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] Pyrrolidine
III
The pharmaceutical salts of formula of the present invention (I) compound, comprise and mineral acid, the salt that example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc. are formed, with organic acid, as the salt that acetic acid, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid etc. are formed, and the amino acids formed salt such as L-Ala, aspartic acid, Methionin or and sulfonic acid, as the salt that methylsulfonic acid, tosic acid etc. are formed.Also their an alkali metal salt, alkaline earth salt, silver salt, barium salt etc. can be prepared by method for transformation routinely.
Another object of the present invention is to provide the preparation method of the compounds of this invention or its pharmaceutical salts and is preparing the application in prevention and therapy mental disorder medicine.
The preparation method of compound or pharmaceutically acceptable salt thereof of the present invention, comprises the steps:
(1) extract: great Ye Betel medicinal material extraction using alcohol, extracting solution obtains great Ye Betel medicinal extract through concentrating under reduced pressure;
(2) be separated: after medicinal extract alcohol solution dissolves, through macroporous adsorbing resin for purification, silicagel column is separated, and obtains the mixture of compound (II) and compound (III);
(3) purifying: mixture obtains compound (II) and compound (III) monomer through efficient preparation liquid phase separation.
Wherein, in step (1), the upper part of described great Ye Betel is cut into medicine materical crude slice; Add the 70%-95% alcohol reflux of 4 ~ 10 times of medicinal material amount volumes, decoct 1.5 ~ 3.5 hours, filter; The dregs of a decoction continue to decoct 1 ~ 3 hour with 3 ~ 8 times amount ethanol, filter; Merging filtrate, decompression recycling ethanol, is concentrated into the medicinal extract that relative density is 1.30 ~ 1.38 (60 DEG C);
In step (2), cross AB-8 macroporous adsorptive resins, crude drug and macroporous resin weight ratio are 5: 1 ~ 1: 1, first use 50% alcohol flushing of 3 ~ 8 times amount column volumes; Then use 70% ~ 95% ethanol elution of 2 ~ 8 times amount, elutriant concentrates to obtain medicinal extract, and it is petroleum ether-ethyl acetate 6: 1 ~ 1: 2 that silicagel column is separated moving phase used.
The present invention also comprises, the pharmaceutical composition containing the compounds of this invention or its pharmaceutical salts.
Pharmaceutical composition of the present invention, can apply with other antidepressant medicament combinations.
In addition, in pharmaceutical composition of the present invention, except containing except the compounds of this invention, one or more in following prevention and therapy mental disorder medicine can also be comprised: as ten thousand daraf(reciprocal of farad) stars, nefazodone, Sulpiride, alprazolam, roller, buspirone, Tandospirone, Methylphenidylacetate, fluoxetine, paroxetine, Sertraline, citalopram, come that scholar is general, fluvoxamine, Reboxetine, Venlafaxine, flupenthixol, melitracen, road sorrow are safe.
Pharmaceutical composition of the present invention can be any medicament forms taken: as: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, pulvis, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.
Pharmaceutical composition of the present invention, the preferably pharmaceutical dosage forms of unitary dose.
Pharmaceutical composition of the present invention, when making medicament, the medicament of unitary dose can contain pharmaceutically active substance 0.1-1000mg of the present invention, and all the other are pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can be the 0.01-99.99% of total formulation weight amount by weight.
Composition of the present invention in use according to the situation determination usage and dosage of patient, as 1-3 time on the one.A 1-10 sheet etc.
Preferably, composition of the present invention is oral preparations or injection.
Wherein, described oral preparations is selected from the one in capsule, tablet, dripping pill, granule, concentrated pill, oral liquid and mixture.
Wherein, described injection is selected from the one in injection liquid, lyophilized injectable powder and aqueous injection.
Pharmaceutical composition of the present invention, the preparation of its oral administration can containing conventional vehicle, and such as tackiness agent, weighting agent, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent, can carry out dressing to tablet if desired.
The weighting agent be suitable for comprises Mierocrystalline cellulose, mannitol, lactose and other similar weighting agent.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivative, such as sodium starch glycollate.Suitable lubricant comprises, such as Magnesium Stearate.The suitable acceptable wetting agent of medicine comprises sodium lauryl sulphate.
Pharmaceutical composition of the present invention, by mixing, is filled, and the method that compressing tablet etc. are conventional prepares solid oral composition.Repeatedly mix and active substance can be made to be distributed in those compositions of a large amount of weighting agent of whole use.
The form of oral liquid can be such as water-based or oily suspensions, solution, emulsion, syrup or elixir, or can be the composite drying products of a kind of used water before use or other suitable carrier.This liquid preparation can containing conventional additive, such as suspension agent, such as sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agent, such as Yelkin TTS, anhydro sorbitol monooleate or gum arabic; Non-aqueous carrier (they can comprise edible oil), the oily ester of the such as ester of Prunus amygdalus oil, fractionated coconut oil, such as glycerine, propylene glycol or ethanol; Sanitas, such as para hydroxybenzene methyl esters or propylparaben or Sorbic Acid, and if need, can containing conventional flavouring agent or tinting material.
For injection, the fluid unit dosage form of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this compound can be suspended or dissolve.The preparation of solution is normally by being dissolved in a kind of carrier by active substance, filter-sterilized before being loaded a kind of suitable bottle or ampoule, then seals.Auxiliary material such as a kind of local anesthetic, sanitas and buffer reagent also can be dissolved in this carrier.In order to improve its stability, by freezing for this composition after loading bottle, and under vacuo water can be removed.
Pharmaceutical composition of the present invention, applicable medicine acceptable carrier is optionally added when being prepared into medicament, described medicine acceptable carrier is selected from: N.F,USP MANNITOL, sorbyl alcohol, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamins C, EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its derivates, alginate, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate etc.
Below by way of experimental data, compound of the present invention and the beneficial effect of composition in prevention and therapy mental disorder thereof are described.
Experiment one, multiple dosing are on the impact of mouse tail suspension dead time
(1) experiment material
1. medicine
Compound (II), compound (III) add the 2%Tween80 aqueous solution, are mixed with the solution containing medicine 1mg/ml.Fluoxetine Hydrochloride, manufacturer: PatheonFrance (France); Divide package plant: Li Lai Suzhou pharmaceutical Co. Ltd; Specification: 20mg/ grain; Lot number: 81958, the interim solution becoming to contain medicine 1mg/ml with 2%Tween80 solution.
2. animal
C57BL/6 mouse, laboratory animal production licence: SCXK (capital) 2006-0009.
3. laboratory apparatus
YLS-1A Multifunctional mouse autonomic activities registering instrument, Shandong Academy of Medical Sciences's equipment station
(2) method and result
C57BL/6 mouse, male, in mouse 6-8 in age week, body weight 18-22g, adaptability was fed after 1 ~ 2 day, mouse was put into YLS-1A Multifunctional mouse autonomic activities registering instrument, recorded 1min end to the movable number of times of mouse in 4min after adapting to 1min.Filter out autonomic activities and be divided into 3 groups at random 30 mouse of 70-150 time, by table 2 list medicine and dosage gastric infusion every day 1 time, successive administration 7 days.Each treated animal is after last administration 60min, and by mouse tail end 1cm place's immobilization with adhesive tape on upholder, make it be reversal of the natural order of things state, its head destage face is about 10cm, by the sight line of plate space between adjacent animal.Mouse in order to overcome abnormal position and struggle activity, but occurs that discontinuity is motionless after movable for some time, shows disappointed state.Every animal observes the time accumulative motionless in 6min, is the disappointed time.Dead time refers to that mouse all limbs except breathing are all motionless.The results are shown in Table 2.
Table 1 shows, 20mg/kg doses of compound (II) and compound (III) administration obviously can shorten the mouse tail suspention dead time for 7 days, have statistical significance (P < 0.05) compared with Vehicle controls group.
Table 1 compound multiple dosing is on the impact of Tail suspension test dead time
Note: compare * P < 0.05, * * P < 0.01 with solvent group
Test two, blepharoptosis and akinetic impact are caused on serpentine
(1) test materials
1. medicine
Compound (II) and (III), fluoxetine, serpentine injection liquid, ShangHai Fudan Fuhua Pharmaceutical Co., Ltd produces, specification 1mg/ml, lot number x070302.
2. animal
Male and female half and half SPF level 6 ~ 8 weeks C57BL/6 mouse, laboratory animal production licence: SCXK (capital) 2006-0009.
(2) method and result
70 male and female half and half C57BL/6 mouse are divided into 7 groups at random, by table 3 list medicine and dosage gastric infusion every day once, continuous 7 days.Mouse, after last administration 1h, by 4mg/kg abdominal injection serpentine, is put in the circular filter paper central authorities that diameter is 7.5cm, observes the number still in filter paper in 30s Nei Ge race animal, calculate the rate that goes too far by each treated animal.Observe each group of mouse can not to open eyes in 2min situation simultaneously, calculate the scoring of eye closing degree according to table 2.The results are shown in Table 3.
Table 2 serpentine causes blepharoptosis standards of grading
The eye closing degree of observing Standards of grading
Eyes full cut-off 4 points
Eyes close 3/4 3 points
Eyes close 2/4 2 points
Eyes close 1/4 1 point
Eyes do not close 0 point
Table 3 multiple dosing causes the impact of blepharoptosis to serpentine
*：P＜0.05；**：P＜0.01
Serpentine antagonism (reserpinereversal) is a kind of vesica reuptake inhibitor.Mouse peritoneal injection serpentine, can make biogenic amine in brain (norepinephrine, 5-HT, Dopamine HCL) exhaust can inducing mouse blepharoptosis, action can not with the phenomenon such as temperature decline, and can by thymoleptic, oxidase inhibitor and central stimulant resist.Table 3 shows, and compound (II) and compound (III) high and low dose successive administration have remarkable antagonism serpentine induced mice blepharoptosis after 7 days and motion can not act on.
Therefore, the present invention also comprises the compounds of this invention or its pharmaceutical salts and the composition application in prevention and therapy mental disorder, particularly dysthymia disorders and anxiety disorder.
Accompanying drawing explanation
Fig. 1 is the uv absorption spectra of the compounds of this invention (II)
Fig. 2 is the infrared spectrogram of the compounds of this invention (II)
Fig. 3 is the high resolution mass spectrum figure of the compounds of this invention (II)
Fig. 4 is the hydrogen spectrum of the compounds of this invention (II)
Fig. 5 is the carbon spectrum of the compounds of this invention (II)
Fig. 6 is the H-H of the compounds of this invention (II), COCY spectrum
Fig. 7 is the HMQC spectrogram of the compounds of this invention (II)
Fig. 8 is the HMBC spectrogram of the compounds of this invention (II)
Fig. 9 is the uv absorption spectra of the compounds of this invention (III)
Figure 10 is the infrared spectrogram of the compounds of this invention (III)
Figure 11 is the high resolution mass spectrum figure of the compounds of this invention (III)
Figure 12 is the hydrogen spectrum of the compounds of this invention (III)
Figure 13 is the carbon spectrum of the compounds of this invention (III)
Figure 14 is the H-H of the compounds of this invention (III), COCY spectrum
Figure 15 is the HMQC spectrogram of the compounds of this invention (III)
Figure 16 is the HMBC spectrogram of the compounds of this invention (III)
Embodiment
Below in conjunction with embodiment, the invention will be further elaborated.The object of these embodiments only for exemplifying, instead of limit the present invention by any way.
Embodiment one
(1) extract: the upper part of 2kg great Ye Betel is cut into medicine materical crude slice; Add 8L70% alcohol reflux, decoct 1.5 hours, filter; Dregs of a decoction continuation 6L ethanol decocts 1 hour, filters; Merging filtrate, decompression recycling ethanol, (relative density is 1.30 (60 DEG C), amounts to 28g to be concentrated into medicinal extract;
(2) be separated: after medicinal extract alcohol solution dissolves, cross AB-8 macroporous adsorptive resins, crude drug weight ratio macroporous resin weight is 5: 1, first uses 50% alcohol flushing of 3 times amount column volumes; Then 70% ethanol elution of 2 times amount is used, elutriant concentrates to obtain medicinal extract, it is petroleum ether-ethyl acetate 6: 1 that silicagel column is separated moving phase used, obtain 1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyl] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] the mixture 0.23g of Pyrrolidine;
(3) purifying: mixture obtains compound 1-[(2E through efficient preparation liquid phase separation, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyls] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] Pyrrolidine monomer is respectively 10mg and 21mg.
Embodiment two
(1) extract: the upper part of 5kg great Ye Betel is cut into medicine materical crude slice; Add 50L95% alcohol reflux, decoct 3.5 hours, filter; Dregs of a decoction continuation 40L ethanol decocts 3 hours, filters; Merging filtrate, decompression recycling ethanol, is concentrated into medicinal extract (relative density is 1.38 (60 DEG C)), obtains 60g;
(2) be separated: after medicinal extract alcohol solution dissolves, cross AB-8 macroporous adsorptive resins, crude drug weight ratio macroporous resin weight is 1: 1, first uses 50% alcohol flushing of 8 times amount column volumes; Then 95% ethanol elution of 8 times amount is used, elutriant concentrates to obtain medicinal extract, it is petroleum ether-ethyl acetate 1: 2 that silicagel column is separated moving phase used, obtain 1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyl] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] the mixture 0.5g of Pyrrolidine;
(3) purifying: mixture obtains compound 1-[(2E through efficient preparation liquid phase separation, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyls] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] Pyrrolidine monomer is respectively 22mg and 50mg.
Embodiment three
1) extract: the upper part of 10kg great Ye Betel is cut into medicine materical crude slice; Add 80% alcohol reflux of 8 times of medicinal material amount volumes, decoct 2 hours, filter; The dregs of a decoction continue to decoct 2 hours with 6 times amount ethanol, filter; Merging filtrate, decompression recycling ethanol, is concentrated into medicinal extract 125g, (relative density is 1.33 (60 DEG C));
(2) be separated: after medicinal extract alcohol solution dissolves, cross AB-8 macroporous adsorptive resins, crude drug weight ratio macroporous resin weight is 3: 1, first uses 50% alcohol flushing of 5 times amount column volumes; Then 80% ethanol elution of 3 times amount is used, elutriant concentrates to obtain medicinal extract, it is petroleum ether-ethyl acetate 1: 1 that silicagel column is separated moving phase used, obtain 1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyl] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] the mixture 1.2g of Pyrrolidine;
(3) purifying: mixture obtains compound 1-[(2E through efficient preparation liquid phase separation, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyls] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] Pyrrolidine monomer is respectively 35mg and 120mg.
Embodiment four
1) extract: the upper part of 10kg great Ye Betel is cut into medicine materical crude slice; Add 85% alcohol reflux of 6 times of medicinal material amount volumes, decoct 2 hours, filter; The dregs of a decoction continue to decoct 2 hours with 4 times amount ethanol, filter; Merging filtrate, decompression recycling ethanol, is concentrated into medicinal extract 130g (relative density is 1.35 (60 DEG C));
(2) be separated: after medicinal extract alcohol solution dissolves, cross AB-8 macroporous adsorptive resins, crude drug weight ratio macroporous resin weight is 2.5: 1, first uses 50% alcohol flushing of 4 times amount column volumes; Then 85% ethanol elution of 4 times amount is used, elutriant concentrates to obtain medicinal extract, it is petroleum ether-ethyl acetate 2: 1 that silicagel column is separated moving phase used, obtain 1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyl] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] the mixture 1.25g of Pyrrolidine;
(3) purifying: mixture obtains compound 1-[(2E through efficient preparation liquid phase separation, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyls] Pyrrolidine and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyl] Pyrrolidine monomer is respectively 38mg and 126mg.
Amides new compound of the present invention, through the physico-chemical property of compound, high resolution mass spectrum (QFT-ESI), 1h-NMR, 13the qualification of C-NMR, DEPT, gCOSY, gHMBC, gHMQC and IR collection of illustrative plates, confirms its structure.
The compounds of this invention (II) is pale yellow powder, and compound (III) is pale yellow oil.
High resolution mass spectrum (QFT-ESI) provides compound (II) quasi-molecular ion peak [M+H] +m/z=326.1754, determines that its molecular formula is C 20h 24nO 3, Compound II per quasi-molecular ion peak [M+H] +m/z=329.1907, determines that its molecular formula is C 20h 25nO 3.
Compound (II) 1h (500M, CDCL 3) and 13c-NMR (125M, CDCL 3) attribution data
Compound (III) 1h (500M, CDCL 3) and 13c-NMR (125M, CDCL 3) attribution data
7 × CH is there is in DEPT spectrum display compound (II) molecule 2, 8 × CH, 3 × C; 9 × CH is there is in compound (III) molecule 2, 6 × CH, 3 × C
IR shows: in compound (II) 3443,1613,1244cm -1show, in structure, there is secondary amide, 1501,808cm -1show, in structure, there is phenyl ring.In compound (III) 3437,1613,1244cm -1show, in structure, there is secondary amide, 1501,808cm -1show, in structure, there is phenyl ring.
By compared with the prior art and correlation spectroscopy contrast, find the compounds of this invention (II) and (III) in spectroscopy respectively with known compound laetispiamideA ((2E, 4E)-N-isobutyl--9-(3,4-MDB) seven carbon diene amides) and laetispiamideB ((2E, 4E, 7E)-N-isobutyl--9-(3,4-MDB) nine carbon diene amides) close, difference is compound laetispiamideA's and laetispiamideB 1be isobutyl-proton signal in H-NMR, and be Pyrrolidine proton signal in the compounds of this invention (II) and compound (III).
So, by compared with the prior art, the compounds of this invention is two new amidess, is respectively: 1-[(2E, 4E, 7E)-9-(3,4-MDB) nine carbon diene acyls] Pyrrolidine, i.e. compound (II) and 1-[(2E, 7E)-N-7-(3,4-MDB) nine carbon diene acyls] Pyrrolidine, i.e. compound (III).

Claims (8)

1. the following compound or pharmaceutically acceptable salt thereof of structure:
2. the preparation method of compound or pharmaceutically acceptable salt thereof described in claim 1, is characterized in that: comprise the steps:
(1) extract: great Ye Betel medicinal material extraction using alcohol, extracting solution obtains great Ye Betel medicinal extract through concentrating under reduced pressure;
(2) be separated: after medicinal extract alcohol solution dissolves, through macroporous adsorbing resin for purification, silicagel column is separated, and obtains the mixture of compound (II) and compound (III);
(3) purifying: mixture obtains compound (II) and compound (III) monomer through efficient preparation liquid phase separation;
In described step (1), the upper part of described great Ye Betel is cut into medicine materical crude slice; Add the 70%-95% alcohol reflux of 4 ~ 10 times of medicinal material amount volumes, decoct 1.5 ~ 3.5 hours, filter; The dregs of a decoction continue to decoct 1 ~ 3 hour with 3 ~ 8 times amount ethanol, filter; Merging filtrate, decompression recycling ethanol, is concentrated into the medicinal extract that relative density is 1.30 ~ 1.38 when 60 DEG C;
In described step (2), cross AB-8 macroporous adsorptive resins, crude drug and macroporous resin weight ratio are 5:1 ~ 1:1, first use 50% alcohol flushing of 3 ~ 8 times amount column volumes; Then use 70% ~ 95% ethanol elution of 2 ~ 8 times amount, elutriant concentrates to obtain medicinal extract, and it is petroleum ether-ethyl acetate 6:1 ~ 1:2 that silicagel column is separated moving phase used.
3. the pharmaceutical composition containing claim 1 compound or pharmaceutically acceptable salt thereof.
4. the pharmaceutical composition of claim 3, can apply with other antidepressant medicament combinations.
5. the pharmaceutical composition of claim 3, also comprises other antidepressant drugs of at least one.
6. the application of compound or pharmaceutically acceptable salt thereof described in claim 1 in preparation treatment and prevention mental disorder medicine.
7. the application of claim 6, wherein said mental disorder is dysthymia disorders and anxiety disorder.
8. the application of claim 6, wherein said mental disorder is dysthymia disorders.
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CN106176659B (en) * 2015-05-05 2019-07-12 四川科瑞德制药股份有限公司 A kind of Tandospirone enteric coatel tablets and preparation method thereof
CN107011313B (en) * 2016-01-27 2021-11-30 天士力医药集团股份有限公司 Application of substituted cinnamide derivative in preparation of anxiolytic drugs
CN113209165A (en) * 2017-11-01 2021-08-06 苏州颐华生物医药技术股份有限公司 Piper laetispicum extract and preparation method and application thereof

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