WO2009140859A1 - Use of l-stepholidine (l-spd) derivatives - Google Patents

Use of l-stepholidine (l-spd) derivatives Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
dyskinesia
levorotatory
compound
serotonin
group
Prior art date
Application number
PCT/CN2009/000542
Other languages
French (fr)
Chinese (zh)
Inventor
镇学初
莫骄
张海
程建军
金国章
杨玉社
Original Assignee
中国科学院上海药物研究所
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 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2009140859A1 publication Critical patent/WO2009140859A1/en

Links

Classifications

    • 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

Landscapes

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

Abstract

The use of l-Stepholidine (l-SPD) derivatives of formula (I) to prepare the medicine in preventing or treating neural diseases relating to 5-hydroxytryptamine is provided. The neural diseases comprise PD, schizophrenia and dyskinesia which is produced by L-dopa or medicine to treat schizophrenia.

Description

左旋千金藤啶碱 ( /-SPD )衍生物的用途 技术领域 本发明涉及药物化学领域， 具体涉及左旋千金藤啶碱 ( /-SPD )衍生物的 用途。 背景技术 帕金森病（PD )又称震颤麻痹症， 是中枢神经***常见和严重的渐进退 行性疾病。 在 60岁以上人群中发病率达 1.8%。 帕金森病的主要病理变化表 现为中脑黑质（SN )多巴胺能神经元进行性变性、 死亡； 残存神经元内出现 嗜酸性蛋白包涵体（ Lewy body, LB )和营养障碍性神经突（ Lewy neurites ), 导致受其支配的纹状体内多巴胺（DA )大量减少。 当纹状体内 DA含量减少 到一定水平时， 黑质-纹状体 DA神经***丧失其运动调节功能， 出现静止性 震颤、 肌肉僵硬、 运动迟緩和姿势反射受损等临床症状， 部分病人还伴有抑 郁、 认知缺损等精神症状。 临床上该病目前以左旋多巴替代治疗， 緩解症状 为主。但是长期慢性用药后约 30%或更多病人出现耐受而对药物治疗无反应。 而且慢性用药后许多 PD 病人 (40% ~ 60%)出现严重不自主运动或运动障碍 ( dyskinesia )等不良反应， 病人表现为不自主运动， 可累及头、 面部、 四肢 和躯干， 有时表现为单调刻板和不自主动作或肌张力障碍， 以致不得不中止 治疗。 因此， 发现能减少运动障碍的治疗方法或药物是抗 PD治疗的一个热 点和关键。  FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry, and in particular to the use of 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. 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. When the DA content in the striatum is reduced to a certain level, 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. Clinically, the disease is currently treated with levodopa replacement, which is mainly symptomatic. However, about 30% or more of patients with chronic long-term medication develop tolerance and do not respond to medication. Moreover, 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.
运动障碍的发生机制还不完全清楚， 基底节区
Figure imgf000003_0001
D2受体功能不平衡 被认为是其病理生理学基础。 除 DA外， 多种非 DA神经递质也具有重要作 用。 5-羟色胺（5-HT ) 受体在基底节有集中分布， 5-HT1A受体激动剂已被证 明有抗运动障碍作用。 例如 5-HT1A受体激动剂沙立佐坦（sarizotan ) 能减轻 鼠和猴 PD模型的运动障碍， 且已经在 PD病人上进行试验并有较好抗运动 障碍效果。 The mechanism of dyskinesia is not fully understood, the basal ganglia
Figure imgf000003_0001
D 2 receptor functional imbalance is considered to be the basis of its pathophysiology. In addition to 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. For example, 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.
左旋千金藤啶碱 ( /-SPD ) 是从中草药"河谷地不容" （ Stephania intermedica ) 中分离到的天然产物， 属于四氢原小檗碱同类化合物 (tetrahychroprotoberberines, THPBs)。单羟基 -THPBs和无羟基 -THPBs均为 DA 受体拮抗剂，而双羟基 -THPBs具有 Di激动和 D2拮抗的双重药理作用 （Mo et al, Cur. Med. Chem, 2007: in press)„这是国际上发现的首个具有针对 DA受体 双重药理作用的药物。 但是 /-SPD水溶性和脂溶性均很差， 导致其口服难于 吸收， 生物利用度极低。 /-SPD 上述缺点， 使其很难成为药物， 限制了其作 为药物进一步进行开发。 L-Kintoline (/-SPD) 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) „ This is the first drug discovered internationally to have dual pharmacological effects against DA receptors. However, /-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.
为解决 /-SPD的生物利用度较低的问题,中科院药物所化学与药理学科通 过联合攻关， 经过结构改造和构效关系研究， 从 /-SPD衍生物中确定了候选 化合物， 在保证其药效学的前提下， 使其生物利用度经口服已提高到 37%, 彻底解决了生物利用度低的问题 (见申请号为 200710039617.4 的中国专利申 请， 公开号为 CN101037436A)。 上述新的 /-SPD衍生物特别适合于治疗精神 ***症。 发明内容  In order to solve the problem of low bioavailability of /-SPD, the chemical and pharmacological disciplines of the Institute of Pharmacy of the Chinese Academy of Sciences have jointly identified the candidate compounds from the /SPD derivatives through joint research and structural structure-activity relationship studies. Under the premise of ergonomics, the bioavailability has been increased to 37% by oral administration, which completely solves the problem of low bioavailability (see Chinese Patent Application No. 200710039617.4, publication number CN101037436A). The above new /-SPD derivatives are particularly suitable for the treatment of schizophrenia. Summary of the invention
本发明的目的是提供左旋千金藤啶碱衍生物的新用途。  It is an object of the present invention to provide a novel use of a levorotatory quinone derivative.
为此， 本发明提供了由下述通式（I )表示的左旋千金藤啶碱 ( /-SPD ) 衍生物在制备预防或治疗与 5-羟色胺相关的神经***疾病的药物中的用途。
Figure imgf000005_0001
To this end, 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.
Figure imgf000005_0001
( I ) 其中 、 R2分别代表氢、 烷基酰基、 苯酰基、 烷基磺酰基或磷酸基， 其 中所述烷基为 CM烷基。 (I) wherein 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.
上述与 5-羟色胺相关的神经***疾病为帕金森病或精神***症或运动障 碍。  The above neurological diseases associated with serotonin are Parkinson's disease or schizophrenia or motor disorders.
上述与 5-羟色胺相关的神经***疾病中的运动障碍是由左旋多巴引起的 或是由精神***症药物引起的。  The dyskinesia in the above-mentioned serotonin-related neurological diseases is caused by levodopa or by schizophrenia drugs.
所述的精神***症药物包括： 经典类如氯丙嗪， 非经典类如利培酮等。 本发明的用于预防或治疗与 5-羟色胺相关的神经***疾病的 /-SPD衍生 物特别优选如下结构式所示的化合物 （见下表 1 ): 表 1 /-SPD衍生物的结构式  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
化合物  Compound
结构式 名称  Structural name
编号  Numbering
14- ( S ) -2， 10-二乙酰氧基 -3,9-二曱氧基 四氢原小檗碱 14- ( S ) -2, 10-Diacetoxy-3,9-dimethoxyoxytetrahydroprotoberberine
14- ( S ) -2， 10-二丙酰氧基 -3,9-二曱氧基 四氢原小檗碱14- ( S ) -2, 10-Dipropionyloxy -3,9-dimethoxyoxytetrahydroprotoberberine
Figure imgf000005_0002
14- (S) -2， 10-二苯曱酰氧基 -3,9-二曱氧基 四氢原小檗碱
Figure imgf000005_0002
14- (S) -2, 10-Dibenzoyloxy-3,9-dimethoxytetrahydroprotoberberine
Figure imgf000006_0001
Figure imgf000006_0001
14- (S) -2,10-二曱磺酰氧基 -3,9-二曱氧基 四氢原小檗碱 14- (S) -2,10-Dioxasulfonyloxy-3,9-dimethoxyoxytetrahydroprotoberberine
14- (S) -10-羟基 -3,9-二曱氧基 -2-曱磺酰氧 基四氢原小檗碱 14- (S) -10-hydroxy-3,9-dimethoxyoxy-2-sulfonyloxytetrahydroprotoberberine
14- (S) -10-羟基 -3,9-二曱氧基 -2-磷酸氧基 四氢原小檗碱14- (S) -10-hydroxy-3,9-dimethoxyoxy-2-phosphooxytetrahydroprotoberberine
Figure imgf000006_0002
本发明的用于预防或治疗与 5-羟色胺相关的神经***疾病的 /-SPD衍生 物最优选为 14- (S) -2,10-二乙酰氧基 -3,9-二甲氧基四氢原小檗碱或 14- (S) -10-羟基 -3,9-二甲氧基 -2-碑酸氧基四氢原小檗碱。
Figure imgf000006_0002
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.
本发明的优点在于：  The advantages of the invention are:
( 1 )本发明的左旋千金藤啶碱衍生物具有很好的理化性质和口服生物利 用度；  (1) The levorotatory quinone derivative of the present invention has good physical and chemical properties and oral bioavailability;
( 2 )在帕金森病动物模型中证实，上述左旋千金藤啶碱衍生物不仅可显 著减少左旋多巴引起运动障碍的发生，而且对已经产生的运动障碍亦可緩解。 显示了其作为一种全新型抗帕金森病及有关的运动障碍药物的巨大前景， 其 不仅可用于预防或治疗帕金森病、 精神***症等与 5-羟色胺相关的神经*** 疾病， 而且可用于预防或治疗由帕金森病药物或精神***症药物引起的运动 障碍。 (2) It has been confirmed in the animal model of Parkinson's disease that the above-mentioned levorotatory quinone base derivative can not only significantly reduce the occurrence of dyskinesia caused by levodopa, but also alleviate the dyskinesia that has already occurred. It shows great promise as a new type of anti-Parkinson's disease and related dyskinesia drugs, which can be used not only to prevent or treat serotonin-related nervous system such as Parkinson's disease and schizophrenia. It can be used to prevent or treat dyskinesia caused by Parkinson's disease drugs or schizophrenia drugs.
附图说明  DRAWINGS
图 1为慢性给予 PD模型大鼠化合物 1对运动障碍的影响示意图。  Figure 1 is a graphical representation of the effect of Compound 1 on dyskinesia in chronically administered PD model rats.
图 2为给予化合物 1对已形成的 PD运动障碍的影响示意图。  Figure 2 is a graphical representation of the effect of Compound 1 on the dyskinesia of established PD.
图 3为化合物 6对已形成的 PD运动障碍的影响。  Figure 3 shows the effect of Compound 6 on the established PD dyskinesia.
图 4为化合物 1对 PD大鼠旋转的影响。  Figure 4 shows the effect of Compound 1 on the rotation of PD rats.
图 5为化合物 1对 5-羟色胺 1 A受体的亲和力示意图。  Figure 5 is a graphical representation of the affinity of Compound 1 for the serotonin 1 A receptor.
图 6为化合物 1抗运动障碍作用与其对 5-HT1 A受体作用的关系示意图。 具体实施方式  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
实施例 1 14- (S) -2,10-二乙酰氧基 -3,9-二甲氧基四氢原小檗碱（化合 物 1)和 14-(S)-10-羟基 -3,9-二甲氧基 -2-磷酸氧基四氢原小檗碱（化合物 6) 治疗运动障碍药效学实验  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
( 1 )动物  (1) animals
取健康成年 Sprague-Dawley 大鼠（200-250g), 三只一笼， 饲养于温度 21士 2°C环境， 正常昼夜（0600h-1800h给光）， 自由进食进水。  Healthy adult Sprague-Dawley rats (200-250g), three cages, kept at a temperature of 21 ± 2 ° C, normal day and night (0600h-1800h light), free access to water.
PD模型制作： 大鼠用水合氯醛（300 mg/kg, ip)麻醉后， 固定在脑立 体定位仪上。 剪开头皮， 暴露骨缝， 找到前囟。 以前囟为起点， 按下列坐标 ( mm )将 6-羟基多巴胺（ 6-OHDA )注射到中央前脑束（ MFB ): 前后（ AP ), -2.5; 旁开 （L), +2.0; 背腹（DV), -8.5o 6-OHDA可沿 MFB逆行运输到 黑质， 被黑质 DA能神经元摄取使之损毁， 本实验损毁左侧黑质。 6-OHDA 溶解在含 0.05%维生素 C的人工脑脊液中， 浓度为 2 g il。 每只大鼠注射量 为 4 μΐ, 即含 6-OHDA8 g。 注射速度 1 μΐ/min, 注射完后微量注射器停留 2 分钟， 然后緩慢拔出。 在 6-OHDA注射前 30分钟给予 25 mg/kg ( ip )地昔 帕明， 防止去甲肾上腺素能神经元摄取 6-OHDA而损伤。 术后缝合伤口， 给 予 5万单位青霉素（ip ), 置于干净鼠笼中饲养。 手术三周后， 将大鼠置于一 直径 50 cm盆中， 适应 10 ~ 20分钟后， 腹腔注射 0.2 mg/kg阿朴***， 记数 其对侧旋转。 5分钟内对侧旋转大于 20转视为成功的 PD模型， 用于后续的 实验。 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. Previously, the 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 μΐ, ie containing 6-OHDA8 g. The injection speed was 1 μΐ/min. After the injection, 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. After suturing the wound, 50,000 units of penicillin (ip) were administered and placed in a clean cage. Three weeks after the operation, the rats were placed in a 50 cm diameter pot. After 10 to 20 minutes of adaptation, 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.
( 2 ) 药物及配制  (2) Drugs and preparation
左旋多巴 （ L-DOPA )溶于无菌生理盐水， 配成 8 mg/ml无色透明溶液， 溶液中加 15 mg/ml苄丝肼， 按 1 ml/kg将药物腹腔注射至大鼠体内。 羟甲基 纤维素钠 （CMC, 食品级）用蒸微水溶解， 配成 0.5%的溶液。  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.
14- ( S ) -2,10-二乙酰氧基 -3,9-二甲氧基四氢原小檗碱（化合物 1 )研磨 后， 用 0.5% CMC配制成 10 mg/ml的悬浮液， 按 10 ml/kg给大鼠灌胃。  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.
14- ( S ) -10-羟基 -3,9-二甲氧基 -2-碑酸氧基四氢原小檗碱（化合物 6 ), 溶于无菌生理盐水， 配成 8 mg/ml无色透明溶液， 腹腔注射 10mg/kg。 14- ( S ) -10-hydroxy-3,9-dimethoxy-2-indicyloxytetrahydroprotoberberine (Compound 6), dissolved in sterile physiological saline, formulated into 8 mg/ml A clear solution, 10 mg/kg intraperitoneally.
( 3 )给药途径及方式  (3) Routes and methods of administration
L-DOPA组： 每天 1次腹腔注射 8 mg/kg L-DOPA, 连续给药 21天； L-DOPA加化合物 1组： 每天 1次腹腔注射 8 mg/kg L-DOPA, 连续给药 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
21天， 每天给予 L-DOPA之前 20min给大鼠 100 mg/kg化合物 1灌胃； On day 21, 100 mg/kg of compound 1 was administered to rats 100 min before L-DOPA administration daily;
对照组（生理盐水）： 每天 1次， 连续 21天腹腔注射 1 ml/kg无菌生理 盐水。  Control group (saline): 1 ml per day of sterile saline was intraperitoneally administered 21 times a day.
在给药的第 1、 4、 7、 11、 14、 17、 21天记录动物的运动障碍行为， 以 此评价慢性给予化合物 1对运动障碍的影响。 第 24天， 已出现运动障碍的 L-DOPA组动物给予 100 mg/kg化合物 1灌胃， 20min后给予 L-DOPA并记 录运动障碍， 用以评价单次化合物 1对已形成的运动障碍的影响。 运动障碍 用异常不随意运动 （AIM )评分评价。 ( 4 )统计分析 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. On day 24, 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
用 SPSS11.0 软件对实验结果进行统计分析， 包括单因素方差分析 ( one-way ANOVA )和 t检验。 P值小于 0.05被认为有统计学意义。  Statistical analysis of the experimental results was performed using SPSS 11.0 software, including one-way ANOVA and t-test. A P value of less than 0.05 was considered statistically significant.
( 5 )结果  (5) Results
1 )慢性给予化合物 1对运动障碍的影响  1) Effect of chronic administration of compound 1 on dyskinesia
如图 1所示， PD大鼠持续给予 8 mg/kg L-DOPA ( n=6 )出现进行性加重 的运动障碍， 在 17 ~ 21天达到峰值。 而 100 mg/kg化合物 1灌胃可明显减轻 L-DOPA导致的运动障碍，方差分析显示，第 7、 17、 21天化合物 1 + L-DOPA 组（ n=6 ) AIM评分显著低于 L-DOPA组（ * P<0.05 )。  As shown in Figure 1, PD rats continuously received 8 mg/kg L-DOPA (n=6) with progressive exacerbation of dyskinesia, peaking at 17-21 days. Oral administration of 100 mg/kg Compound 1 significantly attenuated L-DOPA-induced dyskinesia. Analysis of variance showed that the AIM score of Compound 1 + L-DOPA group (n=6) on Days 7, 17, and 21 was significantly lower than L- DOPA group (*P<0.05).
2 )给予化合物 1对已形成的运动障碍的影响  2) Effect of Compound 1 on the established dyskinesia
PD大鼠给予 L-DOPA 21天后， 表现出稳定的运动障碍。 第 24天， 给予 该组大鼠 100 mg/kg化合物 1灌胃， 20min后给予 L-DOPA并记录运动障碍 ( n=6 )。  PD rats showed stable dyskinesia after 21 days of L-DOPA administration. On day 24, rats in this group were given 100 mg/kg of Compound 1 and given L-DOPA 20 minutes later and dyskinesia (n=6) was recorded.
结果如图 2所示， 大鼠 AIM评分显著降低 ( * PO.05 ), 表明单次给予 100 mg/kg化合物 1灌胃能减轻已形成的运动障碍。  The results are shown in Figure 2. The rat AIM score was significantly lower (*PO.05), indicating that a single administration of 100 mg/kg of Compound 1 can reduce the dyskinesia that has developed.
3 )给予化合物 6对已形成的运动障碍的影响  3) Effect of compound 6 on established dyskinesia
在已形成运动障碍的大鼠上， 腹腔注射 10mg/kg化合物 6, 15分钟后给 予 8mg/kg左旋多巴， 记录 AIM评分（ n=9 )。 如图 3所示， 化合物 6 +左旋 多巴组 AIM评分显著降低（ * p<0.05 ), 表明化合物 6能减轻左旋多巴导致 的运动障碍。  In rats with dyskinesia, 10 mg/kg of compound 6 was intraperitoneally administered, and 8 mg/kg of levodopa was given 15 minutes later, and the AIM score (n=9) was recorded. As shown in Figure 3, the AIM score of the compound 6 + levodopa group was significantly reduced (* p < 0.05), indicating that compound 6 can alleviate dyskinesia caused by levodopa.
以上实验结果表明， 本发明的化合物不仅能减轻慢性应用 L-DOPA导致 的运动障碍， 而且对已形成的运动障碍也有抑制作用， 因此其对于 PD治疗 中出现的运动障碍副作用具有防治价值。  The above experimental results show that 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.
4 )给予化合物 1对 PD大鼠旋转的影响 PD大鼠给予 100 mg/kg化合物 1灌胃， 20min后给予 8 mg/kg L-DOPA, 记录其旋转行为 （n=6 )。 结果如图 4 所示， 化合物 1 + L-DOPA组与单用 L-DOPA比较无显著差异， 表明化合物 1不影响 L-DOPA的 PD治疗效应。 实施例 2 对 5-羟色胺 1A受体的亲和力 4) Effect of Compound 1 on the rotation of PD rats PD rats were given 100 mg/kg of Compound 1 and given 8 mg/kg L-DOPA after 20 min, and their rotational behavior was recorded (n=6). The results are shown in Figure 4. There was no significant difference between the compound 1 + L-DOPA group and the L-DOPA alone, indicating that the compound 1 did not affect the PD treatment effect of L-DOPA. Example 2 Affinity to the serotonin 1A receptor
在转染有受体的 CHO细胞膜组分用于 [3H] 8-OH-DPAT与 5-HT1A受体 结合的竟争抑制试验。 结果如表 2 和图 5 所示， 表明本发明中的化合物对 5-HT1A受体有良好亲和力。  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.
表 2 /-SPD衍生物对 5-羟色胺 1A受体的亲和力 化合物 5-HT1A亲和力 Table 2 / Affinity of SPD Derivatives to the Serotonin 1A Receptor Compound 5-HT 1A Affinity
编号 IC50 Ki  Reference IC50 Ki
1 227.50士 91.22 184士 73.54 1 227.50 士 91.22 184士 73.54
2 125.50士 16.26 101·5±13·442 125.50 士 16.26 101·5±13·44
3 284.50士 185.97 230士 151.323 284.50 s 185.97 230 s 151.32
4 107.5士 40.31 98士 48.084 107.5士 40.31 98士 48.08
5 140.5士 74.25 113.5士 60.10 实施例 3 化合物 1抗运动障碍作用与其对 5-HT1A受体作用有关 5 140.5士 74.25 113.5士 60.10 Example 3 Compound 1 Anti-dysmotility is related to its action on 5-HT1A receptor
PD大鼠给予 L-DOPA 21天后， 表现出稳定的运动障碍。 第 24天， 给予 该组大鼠 100 mg/kg化合物 1 , 灌胃前分别给予 5-HT广谱（ mesulergine, 美 舒麦角）及 5-HT1A选择性（ WAY 100635 )受体拮抗剂， 20min后给予 L-DOPA 并记录运动障碍（ n=6 )。结果如图 6所示（ Mesul:美舒麦角； Way: Wayl00635 ), 在 5-HT及 5-HT1A受体拮抗剂预处理大鼠， AIM评分显著升高（ * PO.05 ), 表明 5-HT1A受体激活与该化合物对已形成的运动障碍减轻作用有关。  PD rats showed stable dyskinesia after 21 days of L-DOPA administration. On day 24, 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. After 20 minutes, L-DOPA was given and dyskinesia was recorded (n=6). The results are shown in Figure 6 (Mesul: Mesquite; Way: Wayl00635). In the pretreated rats with 5-HT and 5-HT1A receptor antagonists, 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.
实施例 2和 3证明， 本发明化合物对帕金森病有良好的治疗作用， 特别 是对左旋多巴引起的运动障碍有很好的緩解作用， 和这类化合物对 5-HT1A 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

Claims

权利要求 Rights request
1、 由下述通式（I )表示的左旋千金藤啶碱衍生物在制备预防或治疗与 5-羟色胺相关的神经***疾病的药物中的用途， A use of a levorotatory quinone derivative represented by the following formula (I) for the preparation of a medicament for preventing or treating a neurological disease associated with serotonin,
Figure imgf000012_0001
其中 、 R2分别代表氢、 烷基酰基、 苯酰基、 烷基磺酰基或磷酸基， 其 中所述烷基为 CM烷基。
Figure imgf000012_0001
Wherein R 2 represents a hydrogen, an alkyl acyl group, a benzoyl group, an alkylsulfonyl group or a phosphate group, respectively, wherein the alkyl group is a C M alkyl group.
2、如权利要求 1所述的左旋千金藤啶碱衍生物的用途， 其特征是， 所述 的与 5-羟色胺相关的神经***疾病为帕金森病。 The use of the levorotatory quinone derivative according to claim 1, wherein the neurological disease associated with serotonin is Parkinson's disease.
3、如权利要求 1所述的左旋千金藤啶碱衍生物的用途， 其特征是， 所述 的与 5-羟色胺相关的神经***疾病为精神***症。 The use of the levorotatory quinone derivative according to claim 1, wherein the neurological disease associated with serotonin is schizophrenia.
4、如权利要求 1所述的左旋千金藤啶碱衍生物的用途， 其特征是， 所述 的与 5-羟色胺相关的神经***疾病为运动障碍。 The use of the levorotatory quinone derivative according to claim 1, wherein the neurological disease associated with serotonin is dyskinesia.
5、如权利要求 4所述的左旋千金藤啶碱衍生物的用途， 其特征是， 所述 的运动障碍是由左旋多巴引起的或是由精神***症药物引起的。 The use of the levorotatory quinone derivative according to claim 4, wherein the dyskinesia is caused by levodopa or caused by a schizophrenia drug.
6、如权利要求 1-5任一项所述的左旋千金藤啶碱衍生物的用途， 其特征 是， 所述左旋千金藤啶碱衍生物是 14- ( S ) -2,10-二乙酰氧基 -3,9-二甲氧基四 氢原小檗碱、 14- ( S ) -2,10-二丙酰氧基 -3,9-二甲氧基四氢原小檗碱、 14- ( S ) -2,10-二苯甲酰氧基 -3,9-二甲氧基四氢原小檗碱、 14- ( S ) -2,10-二甲磺酰氧 基 -3,9-二甲氧基四氢原小檗碱、 14- ( S ) -10-羟基 -3,9-二甲氧基 -2-甲磺酰氧 基四氢原小檗碱或 14- ( S ) -10-羟基 -3,9-二甲氧基 -2-磷酸氧基四氢原小檗碱。 The use of a levorotatory quinone derivative according to any one of claims 1 to 5, wherein the levorotin derivative is 14-(S)-2,10-diacetyl. Oxy-3,9-dimethoxytetrahydroprotoberberine, 14-(S)-2,10-dipropionyloxy-3,9-dimethoxytetrahydroprotoberberine, 14 - ( S ) -2,10-dibenzoyloxy-3,9-dimethoxytetrahydroprotoberberine, 14-(S)-2,10-dimethylsulfonyloxy-3,9-dimethyl Oxytetrahydroprotoberberine, 14-(S)-10-hydroxy-3,9-dimethoxy-2-methanesulfonyloxytetrahydroprotoberberine or 14-(S)-10- Hydroxy-3,9-dimethoxy-2-phosphoryltetrahydroprotoberberine.
7、如权利要求 6所述的左旋千金藤啶碱衍生物的用途， 其特征是， 所述 左旋千金藤啶碱衍生物是 14- ( S ) -2,10-二乙酰氧基 -3,9-二甲氧基四氢原小檗 碱或 14- ( S ) -10-羟基 -3,9-二甲氧基 -2-磷酸氧基四氢原小檗碱。 The use of the levorotatory quinone derivative according to claim 6, wherein the levorotatory derivative is 14-(S)-2,10-diacetoxy-3. 9-Dimethoxytetrahydroprotoberberine or 14-(S)-10-hydroxy-3,9-dimethoxy-2-phosphoryltetrahydroprotoberberine.
PCT/CN2009/000542 2008-05-19 2009-05-19 Use of l-stepholidine (l-spd) derivatives WO2009140859A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2008100376175A CN101584692A (en) 2008-05-19 2008-05-19 Application of L-stopholidine (L-spd) derivative
CN200810037617.5 2008-05-19

Publications (1)

Publication Number Publication Date
WO2009140859A1 true WO2009140859A1 (en) 2009-11-26

Family

ID=41339747

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/000542 WO2009140859A1 (en) 2008-05-19 2009-05-19 Use of l-stepholidine (l-spd) derivatives

Country Status (2)

Country Link
CN (1) CN101584692A (en)
WO (1) WO2009140859A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014515379A (en) * 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 Hexahydrodibenzo [a, g] quinolizine compound, process for producing the same, pharmaceutical composition and application thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102399166B (en) * 2010-09-10 2016-04-27 山东特珐曼药业有限公司 The Stopholidine of optical siomerism and the preparation method of derivative thereof
CN102250087A (en) * 2011-05-16 2011-11-23 中国药科大学 Use of several tetrahydro-proto-berberine compounds in relief of pain
CN102784146A (en) * 2011-05-19 2012-11-21 复旦大学 Medicinal use of N-phenylquinazolinyl-4-amine derivatives

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 (en) * 2007-04-18 2007-09-19 中国科学院上海药物研究所 L-stepholidine (l-SPD) derivatives, preparation method and usage thereof

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 (en) * 2007-04-18 2007-09-19 中国科学院上海药物研究所 L-stepholidine (l-SPD) derivatives, preparation method and usage thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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 (en) * 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 Hexahydrodibenzo [a, g] quinolizine compound, process for producing the same, pharmaceutical composition and application thereof

Also Published As

Publication number Publication date
CN101584692A (en) 2009-11-25

Similar Documents

Publication Publication Date Title
Calne et al. L-Dopa and parkinsonism
Sloan et al. Fluoxetine as a treatment for emotional lability after brain injury
US5552429A (en) Potentiation of drug response
US3961060A (en) Method and compositions for the treatment of neurological disorders
JP2780834B2 (en) Methods and compositions for treating Parkinson&#39;s syndrome in mammals
JPH05507731A (en) Pharmaceutical compositions for the treatment of substance abuse disorders
KR20130101545A (en) Combinations of serotonin receptor agonists for treatment of movement disorders
US20140271890A1 (en) Controlled-release pharmaceutical composition
JP2022507533A (en) Treatment of pulmonary arterial hypertension associated with pulmonary arterial hypertension and other diseases
EP0317269B1 (en) Antiparkinson ergoline derivatives
WO2009140859A1 (en) Use of l-stepholidine (l-spd) derivatives
WO2020127954A1 (en) Treatment of movement disorders
PT759299E (en) SEROTONIN RESPONSE POTENTIATION
US20140221385A1 (en) Combinations of serotonin receptor agonists for treatment of movement disorders
WO2011133212A1 (en) Methods, compounds and pharmaceutical compositions for treating anxiety and mood disorders
JPS61286326A (en) Medicine for parkinsonism
EP0363403A1 (en) Medicament for schizophrenia
WO2009062374A1 (en) The pharmaceutical use of liquiritigenin for preparing medicine for treating neurodegenerative diseases
JPH08504203A (en) Use of idazoxan and its derivatives for the manufacture of a medicament for treating Parkinson&#39;s disease and its progression
JP3394257B2 (en) Use of efaroxane and its derivatives for the manufacture of a medicament for the treatment of Parkinson&#39;s disease
CA2531810A1 (en) Compositions and methods for the treatment of parkinson&#39;s disease and tardive dyskinesias
CN112691102A (en) Application of baicalein in preventing and treating Parkinson&#39;s disease/Parkinson&#39;s syndrome depression symptoms
KR20050058511A (en) New therapeutic uses of 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno-[2,3-d]pirimidine
Rabey et al. EEG sleep study in Parkinsonian patients under bromocryptine treatment
Dourish et al. Effects of ET 495 (piribedil) on water intake in the rat: evidence for a dopaminergic involvement in thirst

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09749402

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09749402

Country of ref document: EP

Kind code of ref document: A1