WO2009140859A1 - Utilisation de dérivés de la l-stépholidine (l-spd) - Google Patents

Utilisation de dérivés de la l-stépholidine (l-spd) Download PDF

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Publication number
WO2009140859A1
WO2009140859A1 PCT/CN2009/000542 CN2009000542W WO2009140859A1 WO 2009140859 A1 WO2009140859 A1 WO 2009140859A1 CN 2009000542 W CN2009000542 W CN 2009000542W WO 2009140859 A1 WO2009140859 A1 WO 2009140859A1
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WIPO (PCT)
Prior art keywords
dyskinesia
levorotatory
compound
serotonin
group
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PCT/CN2009/000542
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English (en)
Chinese (zh)
Inventor
镇学初
莫骄
张海
程建军
金国章
杨玉社
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中国科学院上海药物研究所
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Publication of WO2009140859A1 publication Critical patent/WO2009140859A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/59—Menispermaceae (Moonseed family), e.g. hyperbaena or coralbead
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61P25/14—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

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to the use of a levorotatory quinone base (/-SPD) derivative.
  • a levorotatory quinone base (/-SPD) derivative BACKGROUND OF THE INVENTION
  • Parkinson's disease (PD) also known as tremor paralysis, is a progressive and severe progressive degenerative disease of the central nervous system. The incidence rate is 1.8% among people over 60 years old.
  • Parkinson's disease The main pathological changes of Parkinson's disease are progressive degeneration and death of mesencephalic substantia nigra (SN) dopaminergic neurons; eosinophilic inclusion bodies (LB) and dystrophic neurites (Lewy) in residual neurons Neurites), resulting in a significant reduction in dopamine (DA) in the striatum of the striatum.
  • SN mesencephalic substantia nigra
  • LB eosinophilic inclusion bodies
  • Lewy dystrophic neurites
  • DA dopamine
  • the nigrostriatal striatum DA system loses its motor regulation function, and clinical symptoms such as resting tremor, muscle stiffness, bradykinesia and impaired posture reflex occur, and some patients also There are mental symptoms such as depression and cognitive impairment.
  • the disease is currently treated with levodopa replacement, which is mainly symptomatic.
  • levodopa replacement which is mainly symptomatic.
  • about 30% or more of patients with chronic long-term medication develop tolerance and do not respond to medication.
  • many PD patients (40% to 60%) have severe adverse reactions such as involuntary movement or dyskinesia after chronic administration.
  • the patient exhibits involuntary movement, which may affect the head, face, limbs and trunk, sometimes monotonous.
  • Stereotypes and involuntary movements or dystonias have to stop treatment. Therefore, it has been found that treatments or drugs that reduce dyskinesia are a hot spot and key to anti-PD therapy.
  • the mechanism of dyskinesia is not fully understood, the basal ganglia D 2 receptor functional imbalance is considered to be the basis of its pathophysiology.
  • DA a variety of non-DA neurotransmitters are also important use.
  • the serotonin (5-HT) receptor is concentrated in the basal ganglia, and 5-HT 1A receptor agonists have been shown to have anti-dyskinetic effects.
  • the 5-HT 1A receptor agonist sarizotan can alleviate dyskinesia in the murine and monkey PD models, and has been tested on PD patients with better anti-dyskinetic effects.
  • L-Kintoline is a natural product isolated from the Chinese herbal medicine "Stephania intermedica” and belongs to the class of tetrahydrocharoprotoberberines (THPBs). Both monohydroxy-THPBs and hydroxy-free-THPBs are DA receptor antagonists, while bishydroxy-THPBs have dual pharmacological effects of Di agonism and D 2 antagonism (Mo et al, Cur. Med. Chem, 2007: in press) doctrine This is the first drug discovered internationally to have dual pharmacological effects against DA receptors.
  • /-SPD is poor in water solubility and fat solubility, resulting in poor oral absorption and low bioavailability.
  • /-SPD The above disadvantages, It makes it difficult to become a drug, which limits its further development as a drug.
  • the present invention provides the use of a levorotatory quinone base (/-SPD) derivative represented by the following formula (I) for the preparation of a medicament for preventing or treating a serotonin-related neurological disease.
  • a levorotatory quinone base (/-SPD) derivative represented by the following formula (I) for the preparation of a medicament for preventing or treating a serotonin-related neurological disease.
  • R 2 represents a hydrogen, an alkyl acyl group, a benzoyl group, an alkylsulfonyl group or a phosphoric acid group, respectively, wherein the alkyl group is a C M alkyl group.
  • the above neurological diseases associated with serotonin are Parkinson's disease or schizophrenia or motor disorders.
  • the dyskinesia in the above-mentioned serotonin-related neurological diseases is caused by levodopa or by schizophrenia drugs.
  • the schizophrenia drugs include: classics such as chlorpromazine, non-classical such as risperidone.
  • the /-SPD derivative of the present invention for preventing or treating a serotonin-related neurological disease is particularly preferably a compound represented by the following structural formula (see Table 1 below): Table 1 / Structural formula of the SPD derivative
  • the /-SPD derivative of the present invention for preventing or treating a serotonin-related neurological disease is most preferably 14-(S)-2,10-diacetoxy-3,9-dimethoxytetra Hydrogen berberine or 14-(S)-10-hydroxy-3,9-dimethoxy-2-oyloxytetrahydroprotoberberine.
  • the levorotatory quinone derivative of the present invention has good physical and chemical properties and oral bioavailability
  • Figure 1 is a graphical representation of the effect of Compound 1 on dyskinesia in chronically administered PD model rats.
  • Figure 2 is a graphical representation of the effect of Compound 1 on the dyskinesia of established PD.
  • Figure 3 shows the effect of Compound 6 on the established PD dyskinesia.
  • Figure 4 shows the effect of Compound 1 on the rotation of PD rats.
  • Figure 5 is a graphical representation of the affinity of Compound 1 for the serotonin 1 A receptor.
  • Figure 6 is a graphical representation of the relationship between the anti-dysmotility of Compound 1 and its effect on 5-HT1 A receptor. detailed description
  • Example 1 14-(S) -2,10-Diacetoxy-3,9-dimethoxytetrahydroprotoberberine (Compound 1) and 14-(S)-10-hydroxy-3,9 -Dimethoxy-2-phosphooxytetrahydroprotoberberine (Compound 6) for the treatment of dyskinesia
  • PD model preparation Rats were anesthetized with chloral hydrate (300 mg/kg, ip) and fixed on a brain stereotaxic instrument. Cut the opening skin, expose the suture, and find the front.
  • 6-hydroxydopamine (6-OHDA) was injected into the central forebrain bundle (MFB) at the following coordinates (mm): before and after (AP), -2.5; side-open (L), +2.0; (DV), -8.5o 6-OHDA can be retrogradely transported along the MFB to the substantia nigra, which is damaged by the ingestion of the substantia nigra DA neurons. This experiment damages the left substantia nigra.
  • 6-OHDA is dissolved in artificial cerebrospinal fluid containing 0.05% vitamin C at a concentration of 2 g il.
  • Each rat was injected at 4 ⁇ , ie containing 6-OHDA8 g.
  • the injection speed was 1 ⁇ /min.
  • the micro syringe stayed for 2 minutes and then slowly pulled out.
  • 25 mg/kg (ip) of ground dose 30 minutes before 6-OHDA injection Pamin prevents the noradrenergic neurons from ingesting 6-OHDA and damaging them.
  • 50,000 units of penicillin (ip) were administered and placed in a clean cage.
  • the rats were placed in a 50 cm diameter pot.
  • 0.2 mg/kg apomorphine was intraperitoneally injected, and the contralateral rotation was counted.
  • a contralateral rotation greater than 20 turns in 5 minutes was considered a successful PD model for subsequent experiments.
  • L-DOPA was dissolved in sterile saline solution, and it was formulated into 8 mg/ml colorless transparent solution. 15 mg/ml benserazide was added to the solution, and the drug was intraperitoneally injected into the rat at 1 ml/kg. .
  • Sodium hydroxymethylcellulose (CMC, food grade) was dissolved in steamed water to prepare a 0.5% solution.
  • Compound 1 14-(S)-2,10-Diacetoxy-3,9-dimethoxytetrahydroprotoberberine (Compound 1) was ground and made up to a suspension of 10 mg/ml with 0.5% CMC. Rats were orally administered at 10 ml/kg.
  • L-DOPA group intraperitoneal injection of 8 mg/kg L-DOPA once a day for 21 days;
  • L-DOPA plus compound group 1 intraperitoneal injection of 8 mg/kg L-DOPA once a day, continuous administration
  • Control group 1 ml per day of sterile saline was intraperitoneally administered 21 times a day.
  • the dyskinesia behavior of the animals was recorded on days 1, 4, 7, 11, 14, 17, and 21 of administration to evaluate the effect of chronic administration of Compound 1 on dyskinesia.
  • L-DOPA animals with dyskinesia were given 100 mg/kg of Compound 1 by gavage, and L-DOPA was given 20 min later and dyskinesia was recorded to evaluate the effect of single compound 1 on established dyskinesia.
  • the dyskinesia was evaluated by the abnormal involuntary movement (AIM) score. (4) Statistical analysis
  • Oral administration of 100 mg/kg Compound 1 significantly attenuated L-DOPA-induced dyskinesia.
  • the compound of the present invention not only can alleviate the dyskinesia caused by chronic application of L-DOPA, but also has an inhibitory effect on the formed dyskinesia, and therefore has a preventive value for the side effects of dyskinesia which occurs in PD treatment.
  • the CHO cell membrane fraction transfected with the receptor was used for the competition inhibition assay of [3H] 8-OH-DPAT binding to the 5-HT1A receptor.
  • the results are shown in Table 2 and Figure 5, indicating that the compounds of the present invention have a good affinity for the 5-HT1A receptor.
  • Example 3 Compound 1 Anti-dysmotility is related to its action on 5-HT1A receptor
  • PD rats showed stable dyskinesia after 21 days of L-DOPA administration.
  • rats in this group were given 100 mg/kg of compound 1 and 5-HT broad-spectrum (mesulergine) and 5-HT1A-selective (WAY 100635) receptor antagonists were administered before administration.
  • Figure 6 Mesul: Mesquite; Way: Wayl00635).
  • the AIM score was significantly increased (*PO.05), indicating 5- HT1A receptor activation is associated with a mitigating effect of this compound on established dyskinesia.
  • Examples 2 and 3 demonstrate that the compounds of the invention have a good therapeutic effect on Parkinson's disease, in particular Is a good mitigation effect on dyskinesia caused by levodopa, and such compounds for 5-HT1A

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
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  • Microbiology (AREA)
  • Mycology (AREA)
  • Psychiatry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur l'utilisation de dérivés de la l-stépholidine (l-SPD), de formule (I) pour préparer le médicament dans la prévention ou traitement de maladies neurales liées à la 5-hydroxytryptamine. Les maladies neurales comprennent la maladie de Parkinson, la schizophrénie et la dyskinésie qui est produite par L-dopa ou un médicament de traitement de la schizophrénie.
PCT/CN2009/000542 2008-05-19 2009-05-19 Utilisation de dérivés de la l-stépholidine (l-spd) WO2009140859A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200810037617.5 2008-05-19
CNA2008100376175A CN101584692A (zh) 2008-05-19 2008-05-19 左旋千金藤啶碱(l-SPD)衍生物的用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014515379A (ja) * 2011-05-27 2014-06-30 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ ヘキサヒドロジベンゾ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102399166B (zh) * 2010-09-10 2016-04-27 山东特珐曼药业有限公司 光学异构的千金藤啶碱及其衍生物的制备方法
CN102250087A (zh) * 2011-05-16 2011-11-23 中国药科大学 几种四氢原小檗碱类化合物的镇痛用途
CN102784146A (zh) * 2011-05-19 2012-11-21 复旦大学 N-苯基喹唑啉-4-胺类衍生物的药用用途

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US20040156932A1 (en) * 2003-02-07 2004-08-12 Jie Wu Method for decreasing nicotine and other substance use in humans
CN101037436A (zh) * 2007-04-18 2007-09-19 中国科学院上海药物研究所 左旋千金藤啶碱(l－SPD)衍生物、其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040156932A1 (en) * 2003-02-07 2004-08-12 Jie Wu Method for decreasing nicotine and other substance use in humans
CN101037436A (zh) * 2007-04-18 2007-09-19 中国科学院上海药物研究所 左旋千金藤啶碱(l－SPD)衍生物、其制备方法和用途

Non-Patent Citations (1)

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Title
WU, DUOCHEN ET AL.: "A double-blind comparison trial of I-stepholidine in the treatment of schizophrenia inpatients", MEDICINE WORLD, vol. 7, no. 7, July 2005 (2005-07-01), pages 643 - 646 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014515379A (ja) * 2011-05-27 2014-06-30 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ ヘキサヒドロジベンゾ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用

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