CN1332656C - Application of compound laetispicine in the process for preparing pharmaceutical composition - Google Patents

Application of compound laetispicine in the process for preparing pharmaceutical composition Download PDF

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CN1332656C
CN1332656C CNB2004100254930A CN200410025493A CN1332656C CN 1332656 C CN1332656 C CN 1332656C CN B2004100254930 A CNB2004100254930 A CN B2004100254930A CN 200410025493 A CN200410025493 A CN 200410025493A CN 1332656 C CN1332656 C CN 1332656C
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reuptake
laetispicine
isobutyl
methylendioxyphenyl
udecaetrienamide
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CN1593399A (en
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潘胜利
钱伏刚
王峻
孙凤艳
解静
邵衣慈
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Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

The present invention belongs to the field of the pharmacy of traditional Chinese medicine, which relates to an application of a compound of laetispicine for preparing medicine compounds of inhibiting monoamine transmitter reuptake related diseases of the central nerve system. The present invention proves that the compound can inhibit the reuptake of the synaptosome of the mouse cerebrum to 5-hydroxytryptamine, dopamine and norepinephrine by the test of the monoamine transmitter reuptake of the central nervous system using isotopic elements for marking. The compound of laetispicine of the present invention can be used as raw material for preparing the medicine compounds of inhibiting the monoamine transmitter reuptake related diseases of the central nerve system; the prepared medicine is used for treating related diseases caused by the monoamine transmitter reuptake of the central nervous system.

Description

The application of chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in pharmaceutical compositions
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to a kind of application of amides compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in pharmaceutical compositions that from the plant Piper laetispicum C.DC., is separated to.Be specifically related to the purposes of LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in preparation inhibition central nervous system monoamine transmitters reuptake relevant disease pharmaceutical composition.
Background technology
Along with people's quality of life and improving constantly of health level, system's illness such as nerve, spirit, cardiovascular and endocrine have become the multiple disease of world today's harm humans health, bring white elephant to human society.5-hydroxy tryptamine (5-HT), dopamine (DA) and norepinephrine (NE) are topmost central nervous system's monoamine transmitters.Their content in brain is being controlled human emotion, emotion, is regulating cardiovascular and endocrine function, and with human body temperature, sleep, ingest and motor system relevant.Main metabolic pathway after monoamine neurotransmitter discharges is a reuptake, thus the normal contents of such mediator synaptic space in the control brain.Because the reuptake of monoamine transmitters is unusual, causes the reduction of central nervous system interior 5-HT, NE and DA content, thereby cause the imbalance of nervous system, cardiovascular system, learning and memory function, endocrine and motor system.Comprise: manic or aspects such as depressibility mental disorder, dyssomnias, pain, the dyskinesia and sexual hypofunction.At present, all kinds of relevant chemicalses still can not satisfy the needs of growing clinical treatment.
It is reported that the medicine of excavating antidepressant and treatment mental disorder disease in China's natural drug has formed the research focus.The analgesia of extract tool, calmness and the antidepressant effect of discovering alcohol extraction ethyl acetate extraction from the Chinese medicine Piper laetispicum C.DC. are arranged.
Summary of the invention
The purpose of this invention is to provide a kind of application of amides compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE (Laetispicine) in pharmaceutical compositions that from the plant Piper laetispicum C.DC., is separated to.Be specifically related to the new purposes of chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in the reuptake relevant disease pharmaceutical composition of preparation inhibition central nervous system monoamine transmitters 5-HT, NE and DA.
The present invention's extraction separation from Piperaceae plant Piper laetispicum C.DC. Piper laetispicum C.DC. obtains chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE (Laetispicine), test by with isotope-labeled central nervous system's monoamine transmitters reuptake test confirms that it can suppress the reuptake of the synaptosome of rat brain to 5-hydroxy tryptamine, dopamine and norepinephrine.Chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE of the present invention can be used as raw material, make the pharmaceutical composition that suppresses central nervous system's monoamine transmitters reuptake relevant disease, or make the pharmaceutical composition of the inhibition central nervous system monoamine transmitters reuptake relevant disease that contains a kind of excipient at least, comprise preparations such as capsule, tablet, injection, oral liquid, inhalant, slow releasing agent.Be used for the treatment of the relevant disease that causes because of central nervous system's monoamine transmitters reuptake.
Employed raw medicinal herbs is root, rhizome, stem, leaf, flower or the fruit of Piperaceae plant Piper laetispicum C.DC. Piper laetispicumC.DC..
Described relevant disease comprises, because of 5-hydroxy tryptamine reuptake or synaptic space 5-HT content reduce depression, mandatory psychosis, phobia, anxiety neurosis and the symptoms such as hypertension, insomnia or pain that cause; Reduce depression, anxiety neurosis, mandatory psychosis, dyskinesia disease, neurodegenerative disease (Parkinson's disease, shaking palsy) and the sexual hypofunction etc. that cause because of dopamine reuptake or synaptic space DA content; Because of norepinephrine reuptake or synaptic space NE content reduce the manic depressibility mental disorder, anxiety neurosis, lethargy, damage in learning and memory, the presenile dementia that cause, cardiovascular system diseases (as: low excessively bradycardia, the hypotension that causes of sympathetic nerve brute force) due to unusual, the obesity of ingesting and the autonomic nervous dysfunction and because of sensory function unusual (as indifference to pain), the thermoregulation of sympathetic nerve function due to reducing not normal etc.
The LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE that the present invention relates to (Laetispicine) chemical name: N-isobutyl-11-(3,4-methylend-ioxyphenyl)-2E, 4E, 9E-undecatrienamide, extraction separation obtains from Piperaceae plant Piper laetispicum C.DC. Piperlaetispicum C.DC..By following method extraction separation:
After raw medicinal herbs pulverized, add 95% industrial alcohol reflux, cooled and filtered, residue adds 95% industrial alcohol and carries out secondary back, cold filtration merges filtrate, be evaporated to dried, ethanol extract.Add suitable quantity of water in the ethanol extract, carry out extraction in 1: 1 with petroleum ether, benzene, chloroform, ethyl acetate respectively, reflux, the cooling layering merges each organic facies, and concentrating under reduced pressure obtains petroleum ether extractum, benzene extractum, chloroform extractum, ethyl acetate extractum respectively.Ethyl acetate extractum carries out silica gel column chromatography, carry out gradient elution with cyclohexane extraction-ethyl acetate, obtain six flow point: Fr.I, Fr.II, Fr.III, Fr.IV, Fr.V, Fr.VI, the further column chromatography of Fr.VI wherein, carry out gradient elution with petroleum ether-acetone, collect four flow point: Fr.IV-1, Fr.IV-2, Fr.IV-3, Fr.IV-4, wherein Fr.IV-3 separates out colourless needle, filtration obtains crystal, through HRMS, EIMS, 13CNMR, DEPT, 1HNMR, HMQC, a series of wave spectrums of HMBC, COSY prove N-isobutyl-11-(3,4-methylendioxyphenyl)-2E, 4E, 9E-undecatrienamide, i.e. LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE (1aetispicine).Structural formula is as follows:
Figure C20041002549300051
The The compounds of this invention LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE, the test by with isotope-labeled central nervous system's monoamine transmitters reuptake test confirms that it can suppress the reuptake of the synaptosome of rat brain to 5-hydroxy tryptamine, dopamine and norepinephrine.
Description of drawings
Fig. 1 is that the chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibitory action of the 5-HT reuptake of labelling.
Fig. 2 is that the chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibitory action of the norepinephrine reuptake of labelling.
Fig. 3 is that the chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibitory action of the dopamine reuptake of labelling.
The specific embodiment
Embodiment 1 extraction separation LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE
After the raw medicinal herbs of 1000g pulverized, adds 6 times and measured 95% industrial alcohol reflux 2 hours, cooled and filtered, residue adds 4 times of amount 95% industrial alcohol and carries out secondary back, and cold filtration merges twice filtrate, be evaporated to driedly, obtain ethanol extract 50g.Add suitable quantity of water in the ethanol extract, carry out extraction in 1: 1 with petroleum ether, benzene, chloroform, the ethyl acetate of quintuple respectively, on a small quantity repeatedly, reflux, the cooling layering, merge each organic facies, concentrating under reduced pressure obtains petroleum ether extractum 0.5g, benzene extractum 8g, chloroform extractum 6g, ethyl acetate extractum 10g respectively.The ethyl acetate extractum of 10g carries out silica gel column chromatography, carry out gradient elution with cyclohexane extraction-ethyl acetate (5: 1～3.5: 1.5), obtain six flow point: Fr.I, Fr.II, FR.III, Fr.IV, Fr.V, Fr.VI, the further column chromatography of Fr.IV wherein, carry out gradient elution with petroleum ether-acetone (6: 1～3: 1), collect four flow point: Fr.IV-1, Fr.IV-2, Fr.IV-3, Fr.IV-4, wherein Fr.IV-3 separates out colourless needle, filtration obtains crystal 3 00mg, through HRMS, EIMS, 13CNMR, DEPT, 1HNMR, HMQC, a series of wave spectrums of HMBC, COSY prove N-isobutyl-11-(3,4-methylendioxyphenyl)-2E, 4E, 9E-undecatrienamide, i.e. LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE (laetispicine).
Embodiment 2 isotope-labeled central nervous system's monoamine transmitters reuptake inhibition tests
Get 150-250g Sprague-Dawley male rat, disconnected neck is got brain, peel off the brain district, wherein hypothalamus is used for 5-HT and NE reuptake inhibition experiment, and striatum is used for the DA reuptake and suppresses experiment, weigh, add the ice-cold 0.32M sucrose solution of 25mL/g, ice bath homogenate.The freezing centrifugal 10min of homogenate 1000 commentaries on classics/min discards precipitation, gets supernatant, the freezing centrifugal 20min of 10000-17000 commentaries on classics/min.Precipitation is synaptosome.In aforementioned 0.32M sucrose solution with 10mL/g ratio (pressing brain district tissue wet) suspendible.Measure protein content.Standby.
H 3The monoamine transmitters of labelling is with 200 times of freshly prepared Krebs liquid dilutions.Get 800 μ L+20 μ L medicines (or solvent), mix homogeneously.Add 25 μ L synaptosome suspensions, pick up counting.Behind the 5min with whatman GFB filter paper filtering, and with the washing of ice-cold Krebs liquid.Filter paper oven dry back impouring scintillation solution is measured flicker number of times (CPM) in the per minute.The following 37 degrees centigrade of CPM values of the same terms deduct 0-4 degree centigrade of CPM value and are central nervous system's monoamine transmitters rephotography value.Detection of drugs is to the inhibition situation of monoamine transmitters reuptake.
Above-mentioned sucrose solution contains sucrose 0.32M, EDTA 0.0001M, and glucose 1mg/mL, tris regulates pH value to 7.4.
Described heavy carbonate Krebs reactant liquor wherein composition is,
Composition final concentration (m mol/L)
NaCl 130
KCl 2.74
NaH 2PO 4 0.70
MgCl 2 0.50
NaHCO 3 30
Glucose 10
EDTA 0.171
iproniazid 0.10
pH 7.3
Wherein: (1) .iproniazid is oxidase inhibitor (MAOI), can replace with other, as pargyline.
(2) the .pH value is generally regulated with tris.
4.95%O 2-5%CO 2Saturated.
Described scintillation solution wherein composition is,
PPO 5g，
POPOP 0.2g
Add dimethylbenzene to 1000ml.
Table 1 is that LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibition result of the 5-HT reuptake of labelling.Wherein film CPM value is for deducting the meansigma methods of 3 scinticountings behind the background.
Table 2 is that LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibition result of the NE reuptake of labelling.Wherein film CPM value is for deducting the meansigma methods of 3 scinticountings behind the background.
Table 3 is that LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is to central nervous system in rat H 3The inhibition result of the DA reuptake of labelling.Wherein film CPM value is for deducting the meansigma methods of 3 scinticountings behind the background.
Table 1
The synaptosome position Drug level Film CPM (0 ℃) Film CPM (37 ℃) Suppression ratio (%)
Hypothalamus Control 10514 59393
Hypothalamus 6.7×10 -8mol/L 8476 56654 1.43
Hypothalamus 6.7×10 -7mol/L 8932 52047 11.79
Hypothalamus 6.7×10 -6mol/L 7360 39698 33.84
Hypothalamus 6.7×10 -5mol/L 11683 39646 42.79
Hypothalamus 6.7×10 -4mol/L 10962 35560 49.67
Table 2.
The synaptosome position Drug level Film CPM (0 ℃) Film CPM (37 ℃) Suppression ratio (%)
Hypothalamus Control 5203 33780
Hypothalamus 6.7×10 -8mol/L 5341 27881 21.12
Hypothalamus 6.7×10 -7mol/L 4563 22187 22.39
Hypothalamus 6.7×10 -6mol/L 5521 24675 32.97
Hypothalamus 6.7×10 -5mol/L 5131 20533 46.10
Hypothalamus 6.7×10 -4mol/L 5677 21069 46.14
Table 3.
The synaptosome position Drug level Film CPM (0 ℃) Film CPM (37 ℃) Suppression ratio (%)
Striatum Control 19417 122065
Striatum 1×10 -8mol/L 19680 113552 8.55
Striatum 1×10 -7mol/L 15442 97721 22.76
Striatum 1×10 -6mol/L 18145 78852 40.86
Striatum 1×10 -5mol/L 19440 73467 47.37
Striatum 1×10 -4mol/L 20723 68828 53.14

Claims (4)

1, the chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE suppresses application in central nervous system's monoamine transmitters reuptake relevant disease pharmaceutical composition in preparation treatment, and described relevant disease is to reduce obsession or the phobia that causes because of 5-hydroxy tryptamine reuptake or synaptic space 5-HT content.
2, the chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE suppresses application in central nervous system's monoamine transmitters reuptake relevant disease pharmaceutical composition in preparation treatment, and described relevant disease is to reduce dyskinesia disease or Parkinson's disease or the shaking palsy that causes because of dopamine reuptake or synaptic space DA content.
3, the application of chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in preparation treatment inhibition central nervous system monoamine transmitters reuptake relevant disease pharmaceutical composition; described relevant disease is because of norepinephrine reuptake or synaptic space NE content reduce the damage in learning and memory that causes, unusual, the obesity of ingesting or low excessively bradycardia, the hypotension that causes of sympathetic tone, or unusual or thermoregulation is not normal because of the sensory function of sympathetic nerve function due to reducing.
4, by claim 1 or 2 or 3 described application, wherein said chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is by following method extraction separation:
After the pulverizing of Piper laetispicum C.DC. raw medicinal herbs, the industrial alcohol reflux of adding 95% 2 hours, cooled and filtered, residue adds 95% industrial alcohol and carries out secondary back, cold filtration, merge twice filtrate, be evaporated to dried, obtain ethanol extract, water gagings such as adding are used petroleum ether respectively, benzene, chloroform, ethyl acetate is carried out extraction in 1: 1, reflux, the cooling layering merges each organic facies, and concentrating under reduced pressure gets petroleum ether extractum respectively, benzene extractum, chloroform extractum, ethyl acetate extractum, wherein ethyl acetate extractum carries out silica gel column chromatography, with 5: 1～3.5: 1.5 gradient elutions of cyclohexane extraction-ethyl acetate, get flow point: Fr.I, Fr.II, Fr.III, Fr.IV, Fr.V, Fr.VI, the further column chromatography of Fr.IV wherein, with 6: 1～3: 1 gradient elutions of petroleum ether-acetone, collect flow point: Fr.IV-1, Fr.IV-2, Fr.IV-3, Fr.IV-4, wherein Fr.IV-3 separates out colourless needle, filters to such an extent that crystal is described LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE; Described raw medicinal herbs is selected from root, rhizome, stem, leaf, flower or the fruit of Piperaceae plant Piper laetispicum C.DC. Piper laetispicum C.DC..
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CN102775394B (en) * 2011-05-12 2016-03-09 天士力制药集团股份有限公司 A kind of amides and its preparation method and application
CN104513172B (en) * 2013-09-30 2018-02-02 天士力医药集团股份有限公司 Acid amides alkaloid, preparation method and its medicinal usage containing trifluoromethyl
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