CN102895222B - Applications of 5-(3,4-methylenedioxy phenyl)-2E,4E pentadienoic acid propylamine amide in preparation of neurological disease treatment products - Google Patents
Applications of 5-(3,4-methylenedioxy phenyl)-2E,4E pentadienoic acid propylamine amide in preparation of neurological disease treatment products Download PDFInfo
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Abstract
The present invention relates to uses of 5-(3,4-methylenedioxy phenyl)-2E,4E pentadienoic acid propylamine amide in preparation of medicinal compositions for treatment and/or prevention of neuron diseases requiring neuroprotection effects and/or nerve regeneration. The 5-(3,4-methylenedioxy phenyl)-2E,4E pentadienoic acid propylamine amide provides good treatment effects for depressions caused by various causes, provides significant anti-depression activity for a pharmacological depression model, provides a good protection effect for SH-SY5Y cells damaged by glutamic acid, and provides a selective inhibition effect for monoamine oxidase B (MAO-B).
Description
Technical field
The present invention relates to 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide treat and/or prevent the purposes aspect the product of neurological and/or psychiatric disorders in preparation.
Technical background
Sacred disease is to comprise the disease of the system of affecting the nerves or the medical conditions of obstacle.Sacred disease may be the neural pathology damage with disease or obstacle, or in order to improve cognitive competence, improves the improvement of the neurological function of learning and memory power.
Along with population is day by day aging, oneself becomes the social problem of a serious harm human health to senile dementia (Alzheimerdisease claims again Alzheimer, hereinafter to be referred as AD).The fearful of this disease is that it involves extensively because except patient itself can seriously have a lapse of memory and cognitive competence, also can bring heavy spirit and financial burden for relatives and friends.According to U.S. publilc health mechanism report, the U.S. in 1991 reaches 1,131 hundred million dollars for AD patient's expense, and the direct cost of average every routine AD is annual 4.7 ten thousand dollars, if count indirect expense, every example can consume 17.4 ten thousand dollars.China there is no research report in this respect so far, but has at present more than 600 ten thousand patients, and cost 3000 metaevaluations, at least need to pay every year the expense of tens yuan for each person every year.Have data to show, over-65s prevalence 5%, 80 years old is above up to 20%, so with the aged's continuous growth, AD patient's colony can constantly expand.Therefore, Western society some experts even predict that: in this century, the first killer of posterior lobe harm humans health will be senile dementia.But up till now, medical science, scientific circles still fail to find out the definite cause of disease and effective treatment and prevention method, be therefore put into difficult miscellaneous diseases.
The amplification type neurodegenerative diseases of trinucleotide, nervus retrogression trinucleotide repeats obstacle slowly to carry out, and it is characterized by neuron in motion, sensation or cognitive system is selectivity and loss of symmetry.Symptom ataxia often, dementia or dyskinesia.It is hungtington's chorea that foremost trinucleotide repeats obstacle, and other is that spinal cord and oblongata amyotrophy, autosomal dominant spinocerebellar ataxia are sick.The treatment of HD is devoted to reduce symptom, complication prevention and is provided support and help for patient.Have at present the choreic compound of several available treatments, but there is high risk factor in treatment.
Depression is the main Types of affective disorders, and the remarkable and lasting mental state of take is low is principal character.1996, the investigation about " global disease burden " that World Health Organization (WHO) (WHO) announces showed, nineteen ninety depression become the fourth-largest illness in the world, account for 3.7% of the total burden of whole diseases; And predict the year two thousand twenty and will be only second to ischemic heart desease and become second largest illness, account for 5.7% of the total burden of whole diseases.Depression will be one of disease that the 21 century mankind are the most serious.Existing antidepressant Western medicine is mainly: tricyclic antidepressants (TCAs), and selectivity 5-HT reuptake inhibitor (SSRIs), oxidase inhibitor (MAOIs), the toxic and side effects of their equal various degrees, and expensive.In addition, still have an appointment at present 1/3 depressive patient is not good enough to these antidepressants effects of clinical use.Thereby from Chinese medicine, research and develop new antidepressants and there is important theoretical and practical significance.
Dementia is because large traumatic brain injury or disease face exceed the carrying out property decline that usual aging can calculable cognitive function.Affected especially aspect may be that memory, attention, language and problem solve.Especially in the later stage of disease, affected people may be to time, orientation and people without judgment.Research shows, the reply that neuronal cell generates is relevant in the ability of obtaining trace memory.
Schizophrenia is a kind of with basic personality change, and the division of thinking, emotion and behavior, ergasia and environment are inharmonious is the mental disease of principal character, is one of the most serious disease of facing mankind.In worldwide, lifetime prevalence approaches 1% (difference such as race, region, culture is not remarkable).Schizophrenia causes lifelong misery not only to patient, and causes long-term white elephant to society and family, and schizophrenia accounts for 2.8% of the total burden of global disease, takies a large amount of health care resources.Schizoid main therapy is based on neuroleptics, such as chlorpromazine, haloperidol, olanzapine, clozapine, thioridazine and other.Yet treating effects of diazepam on mice can not alleviate schizoid all symptoms conventionally.And antipsychotic drug treatment may be according to even serious side effect, such as tardive dyskinesia.
Based on technical barrier of the present invention be treatment, improve and/or neurological that prevention is caused by neural degeneration or infringement or inadequate nerve sharp/or the measure of neurological disease.Embodiment by claims and hereinafter description solves described technical barrier.
Summary of the invention
The present invention discloses 5-(3,4-methylenedioxyphenyl)-2E first, and 4E penta 2 diluted acid n-propylamine amide are for the application at preparation treatment sacred disease product.
Sacred disease is wherein at least one disease that is selected from Alzheimer, depression, nervus retrogression trinucleotide repetition obstacle, nervus retrogression lysosomal storage disease, dementia, schizophrenia and peripheral neuropathy.
5-(3 of the present invention, 4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are a kind of active constituents of medicine, according to conventional preparation process, can be with 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are main active constituent, add conventional excipient, flavoring agent, disintegrating agent, antiseptic, lubricant, wetting agent, binding agent, solvent, thickening agent, solubilizing agent excipient substance, make any dosage form that is suitable for using clinically, as tablet, capsule, granule, oral liquid, injection etc.
Because the present invention discloses 5-(3 first; 4-methylenedioxyphenyl)-2E; the pharmacologic action of 4E penta 2 diluted acid n-propylamine amide Cure of depressions; therefore; by 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide separately or coordinate and make medicament with other active constituents or adjuvant; so long as this medicament is used for the treatment of sacred disease, all belong to protection scope of the present invention.
5-of the present invention (3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide, when making any dosage form, all have the effect for the treatment of sacred disease.Any medicament; if contain 5-(3 in its component; 4-methylenedioxyphenyl)-2E; 4E penta 2 diluted acid n-propylamine amide or only with 5-(3; 4-methylenedioxyphenyl)-2E; 4E penta 2 diluted acid n-propylamine amide separate constituents are prepared patent medicine, need only and indicate or point out the effect with treatment sacred disease, within also belonging to protection scope of the present invention in the signs such as its packing or description or on other any propaganda materials.
5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are synthetic:
(1) take piperine 6.08g, add 20%KOH alcoholic solution 150ml, reflux 6 hours, cooling, the solution of sucking filtration crystallization, the potassium salt that filter cake is piperic acid.On filter cake, adding 210ml water. heating for dissolving a little, removes by filter insoluble matter; Mother solution adds hydrochloric acid and stirs, and piperic acid is all precipitated; Sucking filtration, lyophilization obtain 4.13g piperic acid.Productive rate is 116.70%.
(2) take 1.20g piperic acid in dry round-bottomed flask, add dichloromethane and 4ml thionyl chloride that 150ml is dry, heating reflux reaction 1 hour, distilling under reduced pressure is except desolventizing and unnecessary thionyl chloride, the dichloromethane solution that adds 150mL to contain 4ml n-propylamine, 30 minutes (ice bath) of vigorous stirring reaction, water cyclic washing dichloromethane solution, after water layer is colourless, dichloromethane is removed in distilling under reduced pressure, residue, through silica gel column chromatography and recrystallization, obtains product 1.21g, and productive rate is 65.3%.
N-propylamine 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide
1HNMR(CDCl
3，400MHz)δ：0.97(3H，t，J＝8.0Hz，CH
2-CH
3)，1.55(2H，m，CH
2-CH
3)，3.33(2H，m，-NH-CH
2-CH
2)，5.95(1H，d，J＝16.0Hz,-CH＝CH-CO)，5.97(2H，s，-O-CH
2-O)，6.74-6.97(5H，m，olefinic?and?Ar-H)，7.33-7.37(1H，m，CH＝CH-CO)。
Accompanying drawing explanation
5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide
The specific embodiment
Embodiment 1:5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are to monoamine oxidase inhibitory activity
1. material:
1.1 animals: Wisteria rat, Military Medical Science Institute's animal center provides, the quality certification number: SCXK-(army) 2002-001.
1.2 medicines and reagent piperine (being purchased from medication purchasing supply station, Beijing), purity is 98%.Tlc silica gel H (chemical pure is purchased from Qingdao Marine Chemical Co., Ltd.); Column layer chromatography silicone rubber (SILVER REAGENT, 200-300 order, is purchased from Qingdao Marine Chemical Co., Ltd.); Thin layer chromatography silica gel precoated plate (being purchased from Yantai Chemical Industry Research Inst.); PBS phosphate buffer (being purchased from Beijing Solarbio company); MAO-A inhibitor clorgyline, MAO-B inhibitor selegiline, MAO enzyme reaction substrate kynuramine dihydrobromide, standard substance 4-hydroxy quinoline (being purchased from sigma company).
1.3 instruments and material nuclear magnetic resonance analyser JNM-ECA-400 superconduction instrument (Japan), SHZ-D type water cycle vacuum pump (Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.), RE-3000 Rotary Evaporators (Shanghai Yarong Biochemical Instrument Plant), HW-10 type far-infrared ray drying oven (Beijing Xing Zheng instrument and equipment factory), EQ-250E type ultrasonic cleaner (Kunshan Ultrasonic Instruments Co., Ltd.), ultraviolet detector ST-1031A (Japanese Shimadzu company), electronic balance AEL-160-21 (Japanese shimadzu company), the miniature whirlpool mixed instrument of WH-1 (Shanghai Hu Xi instrument plant), UV-2800H type ultraviolet spectrophotometer (UNICO company), HITACH1850 type spectrofluorophotometer (HIT), T18 type refiner (German IKA company)
2. method
2.1 monoamine oxidase, MAO preparations
With reference to the method for Nesrin etc., go bail for and deposit good rat whole brain tissue (80 ℃ freezing, and the storage time is no more than four months, and liquid nitrogen or ice bath shift).After weighing, by tissue 1: 10 (w/v), add homogenate buffer, ice bath homogenate (in 10ml centrifuge tube).4 ℃, centrifugal 10 minutes of 600g, gets supernatant, is transferred in centrifuge tube, and 4 ℃, centrifugal 30 minutes of 10000g, abandons supernatant, and precipitation is MAO enzyme.Above-mentioned homogenate buffer washing for precipitation, 4 ℃, centrifugal 10 minutes of 1500g, abandons supernatant, and precipitation Eddy diffusion is in 1ml homogenate buffer, and-20 ℃ or-80 ℃ save backup.
2.2. external activity of monoamine oxidase is measured
The hydrogenation catalysate of piperine derivant and piperine derivant is dissolved in a small amount of quantitatively DMSO, being mixed with respectively final concentration in the total system of 1ml enzyme reaction is MAO-A (0,25,50,100,200,400 μ M), MAO-B (0,10,20,30,40,50 μ M).
Coomassie brilliant blue method is measured protein concentration.Standard curve is BSA titer 5,10,15,20, the 25 μ l that get 1mg/ml, sample determination is that MAO enzyme sample is got 10 μ l, each pipe adds respectively normal saline to supply volume to 1ml, add 4ml Coomassie brilliant blue G250 solution, mix, use ultraviolet spectrophotometer at wavelength 595nm place, to measure OD value.
MAO catalytic substrate kynuramine dihydrobromide generates product 4-hydroxy quimoline (4-HQ), therefore use 4-HQ standard solution to make the standard curve of enzyme reaction product.4-HQ standard solution 1,2,3,4, the 5 μ l that get respectively 0.4mg/ml add PBS and supply volume to 1ml.Separately draw respectively PBS buffer 0.905ml, MAO-B or MAO-A inhibitor 10 μ l, the piperine of series concentration and the DMSO solution of derivant 10 μ l thereof and MAO enzyme liquid 25 μ l, mix rear 37 ℃ of water-baths and within 10 minutes, make piperine and derivant thereof fully act on MAO enzyme liquid.The mensuration pipe of each concentration adds 50 μ l substrate solutions.Control tube adds 50 μ l substrate solutions after first adding 0.1ml perchloric acid destructive enzyme to live.Each managed 37 ℃ of water-baths after 30 minutes, except control tube, all added 5M perchloric acid 0.1ml, mixed rear 8000rpm centrifugal 10 minutes, got 0.5ml supernatant and added in 2.5ml NaOH solution, mixed.In excitation wavelength, be 315nm, emission wavelength is under 380nm, to measure its fluorescent value.The 4-HQ of series concentration of take is abscissa, and fluorescent value is vertical coordinate, tries to achieve equation of linear regression, according to 4-HQ standard curve, calculates and measures pipe and control tube enzyme is lived, and with μ g4-HQ/min/mg protein, represents that enzyme lives.
2.3. the IC that suppresses MAO-A and MAO-B activity
50calculate
Enzyme slip-knot really uses meansigma methods ± S.D. to represent.(do not give in vitro 5-(3 with matched group, 4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide to MAO enzyme work intervene) relatively, the piperine or derivatives thereof of variable concentrations optionally has different inhibitory action to MAO-A or MAO-B hypotype, and log concentration and the suppression ratio of compound are linear correlation, pass through equation of linear regression, calculate 5-(3,4-methylenedioxyphenyl)-2E, concentration when 4E penta 2 diluted acid n-propylamine amide are 50% to MAO-A and MAO-B maximum inhibition, is IC
50.
MAO suppression ratio computing formula:
/ matched group MAO is active for suppression ratio (%)=(matched group MAO activity-administration group MAO is active)
IC
50computing formula:
Suppression ratio (%)=a*log concentration+b (R
2at least 0.99)
3. result and discussion
We have taked the method for screening active ingredients of vitro inhibition MAO enzyme reaction, on molecule and cellular level, reflect its curative effect to whole animal, the selection result shows 5-(3,4-methylenedioxyphenyl)-2E, the vitro inhibition IC of the positive propionic acid amide. of 4E penta 2 diluted acid to MAO-A
50be 3.66 μ M, the vitro inhibition IC to MAO-B
50be 0.045 μ M.The vitro inhibition IC of piperine to MAO-A
50be 0.404 μ M, the vitro inhibition IC to MAO-B
50be 0.26 μ M
5-(3,4-methylenedioxyphenyl)-2E, the positive propionic acid amide. of 4E penta 2 diluted acid is that n-propylamine replaces the nitrogen-containing compound that the piperidines group in piperine molecule obtains.This compound is better than piperine to the selective inhibitory of MAO-B.Therefore, after the piperidines group of micromolecule amine replacement piperine, the action target spot of antidepressant activity is clearer and more definite, can improve its inhibitory action to MAO-B, but has weakened the effect of piperine inhibition MAO-A.With piperine comparison, when derivative molecular loses the piperidines group of piperine, compound reduces even to lose to the inhibitory action of MAO-A, therefore infers that the piperidines group in piperine molecule is the active group that suppresses MAO-A.
Embodiment 2:5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide antidepressant activity researchs
1. material:
1.1 120 of animal SPF level Kunming mouses (18-22g), are male.
1.2 medicines and reagent piperine (medication purchasing supply station, Beijing), purity is 98%.DMEM/F12 (1: 1) culture medium (Hyclone company); Tetrazolium bromide (Merck company); Desipramine (being purchased from Sigma company); Corticosterone (Sigma company); Hyclone (Hangzhou Sijiqing Biological Engineering Material Co., Ltd.); PBS (Beijing Solarbio company); Dimethyl sulfoxide (Beijing chemical reagents corporation, lot number is 060730); Thionyl chloride (Beijing chemical reagents corporation); Sulphuric acid (Beijing chemical reagents corporation); Hydrochloric acid (Beijing chemical reagents corporation); Trypsin Beijing Trypsin Amresco0458 subpackage); Penicillin, streptomycin (Huabei Pharmaceutic Co., Ltd).Potassium hydroxide (Beijing chemical reagents corporation); Sodium bicarbonate (Beijing chemical reagents corporation);
1.3 instruments and material MCO215AC type CO
2incubator (SANYO); 3K15 type refrigerated centrifuger (Sigma company); DNM29602G enzyme mark
Analyser (Beijing Pu Lang Technew SA).SH-SY5Y cell strain is provided by Military Medical Science Institute's animal center.
2. method
2.1 mice behavior experiments
2.1.1 Tail suspension test
By mice be divided at random blank group, positive drug group (desipramine 20mgkg-1), piperine group (10,20mgkg-1), n-propylamine group (10,20mgkg-1).Each treated animal is organized dosage gastric infusion every day 1 time, successive administration 7d by each.After last administration 30min, by mouse tail apart from the about 2cm of end place with clip with fixed, make mice reversal of the natural order of things in outstanding boot, its head is from about 5cm at the bottom of case.Mice hangs after 2min, gets started observation, observes and continues 4min, motionless (mice aloft stops struggling, or only the has tiny limb motion) time of mice in this 4min of accumulative total.
2.1.2 mice forced swimming experiment
By mice be divided at random blank group, positive drug group (desipramine 20mgkg-1), piperine group (10,20mgkg-1), n-propylamine group (10,20mgkg-1).Each treated animal is organized dosage gastric infusion every day 1 time, successive administration 7d by each.Each is organized after last administration 30min, and mice is put into high 20cm, in the cylindrical glass cylinder of diameter 14cm, and 1, every cylinder, depth of water 10cm in cylinder, water temperature (25 ± 1) ℃.After mice swimming 2min, start immediately to observe, observe and continue 4min, motionless (mice stops struggling in water, or animal is floating state, only the has tiny limb motion) time in this 4min of accumulative total.
The foundation of 2.2 corticosterone damage SH-SY5Y cell models
With containing 10% hyclone, penicillin 100IUmL-1, the DMEM culture medium of streptomycin 100IUmL-1, at 37 ℃, in the incubator of 5%CO2 saturated humidity, cultivate, the SH-SY5Y cell of exponential phase to be entered reaches 70%～80% and merges, with the about 2min of 0.25% trypsinization, Microscopic observation cell is rounded, cell partly hangs, add immediately with the isopyknic DMEM complete medium of pancreatin and stop digestion, with suction pipe piping and druming cell to cell on culture bottle wall, all blow and beat, with suction pipe, be transferred to 15mL tip centrifuge tube, the centrifugal 3min of 1000rmin-1, abandoning supernatant, DMEM culture medium re-suspended cell, ratio with 1: 3 goes down to posterity.Approximately 1 * 104/mL of cell concentration that regulates SH-SY5Y with cell counter, every hole 80 μ L are inoculated in 96 orifice plates, continue to cultivate.After 48h, every hole adds 10 μ L corticosterone 400 μ molL-1 damages (except blank group and DMSO matched group), and each experimental group is all established 4 multiple holes.
After SH-SY5Y cell culture 2-3d after going down to posterity, after 0.25% trypsinization, be transferred to after centrifugal in 15ml centrifuge tube and abandon supernatant, DMEM culture medium re-suspended cell, with cell counter, regulate approximately 1 * 104/ml of cell concentration, every hole 80 μ L are inoculated in 96 orifice plates, and every hole adds 10 μ L corticosterone damages, continues to cultivate, add the piperine and each medicinal liquid of the derivant 10 μ L that have joined, each experimental group is all established 4 multiple holes.After 24h, stop cultivating, it is the MTT20 μ L of 5mg/ml that every hole adds whole mass concentration, in 37 ℃, 5%CO2 incubator, continue to cultivate 4h, after hepatic knot product form, supernatant is abandoned in suction, and every hole adds DMSO150 μ L, shaking table jolting 10min, fully the bluish violet crystal in dissolved cell, measures 570nm wavelength place absorbance by microplate reader.Data represent with means standard deviation and calculate cell survival rate.
3 results
3.1 piperines and 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 impacts of diluted acid n-propylamine amide on mouse tail suspension and non-swimming time
After administration one week, can obviously shorten the dead time of mice in stress environment, extend the time of outstanding tail, obviously alleviate its desperate behavior state, prompting piperine and derivant n-propylamine thereof have good antidepressant effect.High dose group in piperine group (20mgkg-1) effect is the poorest, demonstrates inverted amount effect relation curve.High dose group in n-propylamine group (20mgkg-1) effect is better than low dose group (10mgkg-1), and the amount effect curve of visible n-propylamine is forward.Meanwhile, experiment shows, the antidepressant effect of n-propylamine derivant is better than piperine.
Table 1 piperine and 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 impacts of diluted acid n-propylamine amide on the mouse tail suspension dead time
(
n＝10)
Note: with the comparison of blank group
1)p < 0.01,
2)p < 0.05.
Table 2 piperine and 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are forced the impact of non-swimming time on mice
(
n＝10)
Note: with the comparison of blank group
1)p < 0.01,
2)p < 0.05.
3.2 piperines and 5-(3,4-methylenedioxyphenyl)-2E, the impact of 4E penta 2 diluted acid n-propylamine amide on SH-SY5Y cell injury due to corticosterone
Because the succinate dehydrogenase in living cells mitochondrion can make exogenous MTT, be reduced to bluish violet crystal and be deposited in cell, and dead cell is without this function, DMSO makes to tie product thing and dissolves, and at 570nm wavelength place, measures its absorbance value (A570nm), can indirectly reflect living cells quantity.Under inverted microscope, observe the metamorphosis of SH-SY5Y cell, the SH-SY5Y cell process of blank group is obvious, is fusiformis, irregular triangle or polygon.The most of cell space shrinkage of negative control group SH-SY5Y cell, projection shortens disappearance or fracture, and cell is rounded.MTT testing result is known, and corticosterone shows obvious damage phenomenon to SH-SY5Y cell, and positive group relatively has significant difference with model group, and medicine group and model group relatively have significant difference.
Table 3. piperine and 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide to corticosterone damage SH-SY5Y cell situation (
n=4) (48h)
Note: with blank group comparison: ##P < 0.01, #P < 0.05; With negative control group comparison: claim P < 0.01, * P < 0.05
3 discuss
In this experiment, 5-(3,4-methylenedioxyphenyl)-2E, 4E penta 2 diluted acid n-propylamine amide are shorter at the outstanding tail non-swimming time of behavioristics's experiment small mouse, and its antidepressant effect is better than piperine and other derivants.
This experiment is the antidepressant on behavioristics's model based on piperine, selects the SH-SY5Y neural cell model of corticosterone damage, observes piperine and the protective effect of derivant to neurocyte thereof.Result of study shows; corticosterone shows obvious damage to SH-SY5Y cell, has piperine and 5-(3,4-the methylenedioxyphenyl)-2E of antidepressant activity; 4E penta 2 diluted acid n-propylamine amide can obviously suppress the damage of corticosterone, present the effect of good neuroprotective cell.
Claims (3)
1. a compound as follows purposes in the Pharmaceutical composition for the preparation for the treatment of Alzheimer
。
2. purposes according to claim 1, refers to and adds conventional flavoring agent, disintegrating agent, antiseptic, lubricant, wetting agent, binding agent, thickening agent, solubilizing agent excipient substance, makes any dosage form that is suitable for using clinically.
3. purposes according to claim 2, is selected from tablet, capsule, granule, oral liquid, injection.
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| Title |
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| 刘屏等.胡椒碱药理作用的研究进展.《中国药物应用与监测》.2007,(第3期),7－8. |
| 崔广智等.胡椒碱抗抑郁作用研究.《辽宁中医药大学学报》.2010,第12卷(第7期),42－43. |
| 胡椒碱抗抑郁作用研究;崔广智等;《辽宁中医药大学学报》;20100731;第12卷(第7期);42－43 * |
| 胡椒碱药理作用的研究进展;刘屏等;《中国药物应用与监测》;20070630(第3期);7－8 * |
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