WO2006000158A1 - Utilisation de laetispicine pour la fabrication d'une composition pharmaceutique - Google Patents

Utilisation de laetispicine pour la fabrication d'une composition pharmaceutique Download PDF

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Publication number
WO2006000158A1
WO2006000158A1 PCT/CN2005/000912 CN2005000912W WO2006000158A1 WO 2006000158 A1 WO2006000158 A1 WO 2006000158A1 CN 2005000912 W CN2005000912 W CN 2005000912W WO 2006000158 A1 WO2006000158 A1 WO 2006000158A1
Authority
WO
WIPO (PCT)
Prior art keywords
reuptake
extract
nervous system
central nervous
monoamine neurotransmitter
Prior art date
Application number
PCT/CN2005/000912
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English (en)
Chinese (zh)
Other versions
WO2006000158A8 (fr
Inventor
Sheng-Li Pan
Fu-Gang Qian
Jun Wang
Feng-Yan Sun
Jing Xie
Yi-Ci Shao
Original Assignee
Fudan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fudan University filed Critical Fudan University
Publication of WO2006000158A1 publication Critical patent/WO2006000158A1/fr
Publication of WO2006000158A8 publication Critical patent/WO2006000158A8/fr

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Classifications

    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—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

Definitions

  • the invention belongs to the field of traditional Chinese medicine and relates to an application of an amide compound daidzein isolated from the plant Eucalyptus urophylla in the preparation of a pharmaceutical composition. Specifically, it relates to the use of macrophyllin for the preparation of a pharmaceutical composition for inhibiting a central nervous system monoamine-based re-uptake-related disease. Background technique
  • Serotonin (5-HT), dopamine (DA) and norepinephrine (NE) are the most important monoamine neurotransmitters in the central nervous system. Their levels in the brain control human emotions, emotions, regulate cardiovascular and endocrine functions, and are related to human body temperature, sleep, food intake, and motor systems. The main metabolic pathway after the release of monoamine neurotransmitters is reuptake, thereby controlling the normal content of synaptic gaps in this brain.
  • Abnormalities in reuptake of monoamine transmitters result in a decrease in 5-HT, NE, and DA levels in the central nervous system, leading to disorders in the nervous system, cardiovascular system, learning and memory, endocrine, and motor systems. These include: manic or depressive disorders, sleep disorders, pain, dyskinesia, and sexual dysfunction. At present, various types of related chemical drugs still cannot meet the needs of increasing clinical treatment.
  • the present invention extracts and isolates Laetispicine from Piper laetispicum C. DC., a pepper plant, by using an isotope-labeled central nervous system monoamine transmitter reuptake test. It was tested to confirm that it inhibits the reuptake of serotonin, dopamine and norepinephrine by synaptosomes in the rat brain.
  • the compound macrophyllin of the present invention can be used as a raw material to prepare a pharmaceutical composition for inhibiting a disease related to reuptake of a monoamine neurotransmitter in the central nervous system, or to inhibit a central nervous system monoamine containing at least one excipient.
  • a pharmaceutical composition for re-intake-related diseases including capsules, tablets, injections, oral solutions, inhalants, sustained release agents and the like. It is used to treat related diseases caused by re-uptake of monoamine transmitters in the central nervous system.
  • the raw medicinal material used is the pepper family C. DC. Roots, rhizomes, stems, leaves, flowers or fruits.
  • the related diseases include depression caused by serotonin reuptake or decreased synaptic 5-HT content, obsessive-compulsive disorder, phobia, anxiety and hypertension, insomnia or pain; dopamine Depression, anxiety, obsessive-compulsive disorder, motor dysfunction, neurodegenerative diseases (Parkinson's disease, tremor palsy), and sexual dysfunction caused by decreased re-intake or decreased synaptic DA content; Cardiovascular depression caused by adrenaline reuptake or decreased synaptic NE content caused by manic depressive disorder, anxiety, narcolepsy, learning and memory dysfunction, Alzheimer's disease, eating abnormalities, obesity and autonomic dysfunction Systemic diseases (such as: bradycardia caused by low sympathetic nerve hypotension, hypotension) and sensory dysfunction caused by decreased sympathetic function (such as painlessness), abnormal body temperature regulation.
  • the present invention relates to Laetispicine chemical name: N-isobutyl-l l-(3,4-methy lend-ioxyphenyl)-2E, 4E, 9E-undecatrienamide, from the pepper-grown plant Big-mouth ten Piper laetispicum C
  • the separation in DC is obtained.
  • the separation is extracted by the following method:
  • Fr. I Fr. II Fr. IIL Fr. IV
  • Fr. V Fr. In VL
  • Fr. IV was further subjected to column chromatography, and gradient elution with petroleum ether-acetone was carried out to collect four fractions: Fr.IV_l, Fr.IV-2, Fr.IV_3, Fr.IV-4, Among them, Fr. IV-3 precipitated colorless needle crystals, and crystals were obtained by filtration.
  • the compound of the present invention is tested by isotopically labeled central nervous system monoamine neurotransmitter reuptake assay, see drawing: Laetispicine antidepressant mechanism study confirmed that it can inhibit synaptosome pairs in rat brain 5 Re-uptake of serotonin, dopamine and norepinephrine. DRAWINGS
  • FIG 1 is a large leaf Jun inhibitory effects of compounds in rats by the central nervous system labeled H 5- HT 3 reuptake.
  • FIG 2 is a large leaf Jun inhibitory effects of compounds in rats by the central nervous system H 3 labeled norepinephrine reuptake. '
  • the hypothalamus was used for 5-HT and NE reuptake inhibition experiments.
  • the striatum was used for DA reuptake inhibition experiments, weighing, 25 mL/g ice-cold 0.32 M sucrose solution was added and the paddle was homogenized in an ice bath. The homogenate was centrifuged at 1000 rpm for 10 min, and the precipitate was discarded. The supernatant was taken and centrifuged at 10,000-17,000 rpm for 20 min. The precipitate is the synapse.
  • the above 0.32 M sucrose solution was suspended at a ratio of lOm! Jg (based on the wet weight of the brain tissue). The protein content was determined. spare.
  • H 3 labeled monoamine neurotransmitters diluted 200-fold in Krebs solution freshly prepared. Take 800 ⁇ L + 20 ⁇ L of drug (or solvent) and mix well. Add 25 ⁇ L of synaptosome suspension and start timing. After 5 min, it was filtered on Whatman GFB filter paper and washed with ice-cold Krebs solution. After the filter paper is dried, pour in the scintillation fluid and measure the number of flashes per minute (CPM). Under the same conditions, the CPM value of 37 degrees Celsius minus the CPM value of 0-4 degrees Celsius is the re-uptake value of the monoamine transmitter in the central nervous system. The inhibition of the reuptake of monoamine transmitters by the drug was examined.
  • sucrose solution contains sucrose 0.32 M, EDTA 0. 0001 M, glucose lmg/mL, tris adjusted pH to 7.4.
  • the bicarbonate Krebs reaction solution is composed of
  • iproniazid is a monoamine oxidase inhibitor (MAOI), which can be replaced by others, such as pargylkie 0
  • the pH is usually adjusted with tris.
  • the scintillation liquid has a composition of
  • Table 1 is a large leaf Yun factor on central nervous system in rats H: i labeled 5- HT reuptake inhibition results.
  • the membrane CPM value is the average of the three scintillation counts after subtracting the background.
  • Table 2 is a large leaf central nervous system drugs in rats by H 3 labeled NE reuptake inhibition results.
  • the membrane CPM value is the average of the three scintillation counts after subtracting the background.
  • Table 3 shows the results of inhibition of H 3 labeled DA reuptake by the central nervous system in rats.
  • the membrane CPM value is the average of the three scintillation counts after subtracting the background.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Reproductive Health (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pregnancy & Childbirth (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne l'utilisation de laetispicineur la fabrication d'une composition pharmaceutique destin inhiber la recapture du neurotransmetteur monoamine du système nrvu central, pour le traitement des maladies associées induitesparlarecapture du neurotransmetteur monoamine du système nerveu cenral
PCT/CN2005/000912 2004-06-25 2005-06-24 Utilisation de laetispicine pour la fabrication d'une composition pharmaceutique WO2006000158A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410025493.0 2004-06-25
CNB2004100254930A CN1332656C (zh) 2004-06-25 2004-06-25 化合物大叶蒟素在制备药物组合物中的应用

Publications (2)

Publication Number Publication Date
WO2006000158A1 true WO2006000158A1 (fr) 2006-01-05
WO2006000158A8 WO2006000158A8 (fr) 2006-02-09

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PCT/CN2005/000912 WO2006000158A1 (fr) 2004-06-25 2005-06-24 Utilisation de laetispicine pour la fabrication d'une composition pharmaceutique

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WO (1) WO2006000158A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101798297B (zh) * 2009-02-11 2013-02-27 中国科学院上海药物研究所 大叶蒟素的化学合成方法
CN102240281B (zh) * 2010-05-12 2014-05-14 天士力制药集团股份有限公司 5′-甲氧基-3′，4′-次甲二氧基桂皮酸异丁基酰胺在制备抗抑郁药物中的应用
CN102775394B (zh) * 2011-05-12 2016-03-09 天士力制药集团股份有限公司 一种酰胺类化合物及其制备方法和应用
CN104513172B (zh) * 2013-09-30 2018-02-02 天士力医药集团股份有限公司 含有三氟甲基的酰胺生物碱、制备方法及其药物用途
CN104940821A (zh) * 2015-06-28 2015-09-30 李先强 一种治疗余光恐惧症的中药

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1389462A (zh) * 2002-07-12 2003-01-08 复旦大学 大叶蒟素及其同系物，和在制备药物组合物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1389462A (zh) * 2002-07-12 2003-01-08 复旦大学 大叶蒟素及其同系物，和在制备药物组合物中的应用

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Publication number Publication date
CN1332656C (zh) 2007-08-22
WO2006000158A8 (fr) 2006-02-09
CN1593399A (zh) 2005-03-16

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