CN1593399A - 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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CN1593399A
CN1593399A CNA2004100254930A CN200410025493A CN1593399A CN 1593399 A CN1593399 A CN 1593399A CN A2004100254930 A CNA2004100254930 A CN A2004100254930A CN 200410025493 A CN200410025493 A CN 200410025493A CN 1593399 A CN1593399 A CN 1593399A
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reuptake
laetispicine
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isobutyl
nervous system
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CN1332656C (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
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A—HUMAN NECESSITIES
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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Abstract

The invention relates to the use of compound Laetispicine in the process for preparing pharmaceutical compositions for suppressing central nerve system monoamine transmitter reuptake related diseases, wherein the compound Laetispicine can be used as raw material for preparing pharmaceutical compositions for inhibiting central nerve system monoamine transmitter reuptake related diseases.

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, FrIII, Fr.V, Fr.VI, the further column chromatography of Fr.IV 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 (laetispicine).Structural formula is as follows:
Figure A20041002549300061
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 one 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 (mmol/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 (8)

1, the application of chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE in preparation inhibition central nervous system monoamine transmitters reuptake relevant disease pharmaceutical composition.
2, by the described application of claim 1, wherein said chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE is by following method extraction separation,
After raw medicinal herbs pulverized, added 95% industrial alcohol reflux 2 hours, cooled and filtered, residue adds 95% industrial alcohol and carries out secondary back, and cold filtration merges twice filtrate, is evaporated to driedly, obtains ethanol extract.Adding waits water gaging in the ethanol extract, use petroleum ether respectively, benzene, chloroform, ethyl acetate is carried out extraction in 1: 1, reflux, the cooling layering, merge each organic facies, 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 cyclohexane extraction-ethyl acetate (5: 1～3.5: 1.5) gradient elution, 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 a LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE.
3,, it is characterized in that described chemical compound LAETISPICINE N-ISOBUTYL-11-(3,4-METHYLENDIOXYPHENYL)-2E,4E,9E-UDECAETRIENAMIDE makes capsule, tablet, injection, oral liquid, inhalant or slow releasing agent as raw material according to the application of claim 1 or 2.
4, the application of claim 2, described raw medicinal herbs are root, rhizome, stem, leaf, flower or the fruits of Piperaceae plant Piper laetispicum C.DC. Piper laetispicumC.DC..
5, the application of claim 1, wherein said central nervous system's monoamine transmitters are 5-hydroxy tryptamine or dopamine or norepinephrine.
6, the application of claim 1, wherein said central nervous system's monoamine transmitters reuptake relevant disease are to reduce depression, mandatory psychosis, phobia, anxiety neurosis or hypertension, insomnia and the pain symptom that causes because of 5-hydroxy tryptamine reuptake or synaptic space 5-HT content.
7, the application of claim 1, wherein said central nervous system's monoamine transmitters reuptake relevant disease is to comprise Parkinson's disease, shaking palsy because of dopamine reuptake or synaptic space DA content reduce the depression, anxiety neurosis, mandatory psychosis, dyskinesia disease, the neurodegenerative disease that cause, or sexual hypofunction.
8, the application of claim 1, wherein said central nervous system's monoamine transmitters reuptake relevant disease is 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 due to unusual, the obesity of ingesting or the autonomic nervous dysfunction comprises low excessively bradycardia, the hypotension that causes of sympathetic nerve brute force, or because of the sensory function due to the sympathetic nerve function reduction comprises indifference to pain unusually, or thermoregulation is not normal.
CNB2004100254930A 2004-06-25 2004-06-25 Application of compound laetispicine in the process for preparing pharmaceutical composition Expired - Fee Related CN1332656C (en)

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