WO2020087685A1 - Application de dérivés d'artémisinine dans la préparation d'un médicament anti-épileptique - Google Patents

Application de dérivés d'artémisinine dans la préparation d'un médicament anti-épileptique Download PDF

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Publication number
WO2020087685A1
WO2020087685A1 PCT/CN2018/121596 CN2018121596W WO2020087685A1 WO 2020087685 A1 WO2020087685 A1 WO 2020087685A1 CN 2018121596 W CN2018121596 W CN 2018121596W WO 2020087685 A1 WO2020087685 A1 WO 2020087685A1
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epilepsy
artemether
preparation
artemisinin
injection
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PCT/CN2018/121596
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English (en)
Chinese (zh)
Inventor
陈永君
许能贵
姚琳
颜靖岚
卢甜
苏杨
吴晓丽
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广州中医药大学(广州中医药研究院)
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Publication of WO2020087685A1 publication Critical patent/WO2020087685A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the invention relates to the technical field of medicine, in particular to the application of artemisia annua derivatives in the preparation of antiepileptic drugs.
  • Epilepsy is a neurological disease caused by a variety of causes. It is characterized by sudden abnormal discharge of brain neurons, resulting in transient brain dysfunction. The seizures manifest as limb convulsions, loss of consciousness, and behavioral disorders. The causes of seizures include brain trauma, stroke, intracranial tumors, intracranial infections, birth defects in newborns, convulsions in children with high fever, and genetic factors. Seizures bring physical and mental pain to patients. Repeated seizures can cause damage to brain tissue and cognitive function, thereby affecting the quality of life, increasing the economic burden of patients' families and society, and severe systemic seizures Cause the patient to die.
  • Temporal lobe epilepsy is the most common type of epilepsy in clinic. It refers to the origin of the temporal lobe including the hippocampus, amygdala, para hippocampal gyrus, and lateral temporal lobe neocortex, accounting for about 30% to 35% of clinical seizures, mainly found in Adults and teenagers.
  • Temporal lobe epilepsy has a long history, frequent seizures, and poor drug control. It usually develops into refractory epilepsy.
  • the methods for treating epilepsy include traditional medical treatment, surgical treatment, nerve stimulation, cell transplantation, gene therapy, etc., but there is still a lack of ideal treatment methods.
  • the application of antiepileptic drugs is still the most important treatment for epilepsy.
  • Traditional antiepileptic drugs such as phenytoin, carbamazepine, valproic acid, phenobarbital, diazepam, etc. have poor efficacy in patients with refractory epilepsy.
  • KA KAnic acid
  • Kinding electrokinetic
  • KA is a powerful analog of glutamic acid, which can induce strong depolarization And eventually lead to cell death.
  • the mouse model of acute epilepsy induced by intraperitoneal injection of KA has similar behavior, brain electrical abnormalities and neuropathological changes as human temporal lobe epilepsy. Electric ignition ignites the same brain area repeatedly with a certain intensity of subthreshold stimulation at a certain time interval, so that the intensity of epileptic activity gradually increases, which can eventually lead to generalized seizures.
  • These two animal models are classic epilepsy animal models.
  • Artemisinin is now recognized as an anti-malarial drug. Although artemisinin has a good antimalarial effect and low toxic side effects, it also has poor water solubility and fat solubility, making it difficult to make a suitable preparation and causing low bioavailability and high reignition.
  • Three commonly used derivatives dihydroartemisinin, artemether, artesunate.
  • Dihydroartemisinin (DHA) is a hydroxy derivative of artemisinin reduced by sodium borohydride. Its molecular formula is C 15 H 24 O 5 and its molecular weight is 284.4. Show.
  • Artesunate is a succinic acid half-ester derivative of dihydroartemisinin with potassium borohydride instead of sodium borohydride in the reduction of artemisinin. Its molecular formula is C 19 H 28 O 8. The molecular weight is 384.4.
  • the chemical structure of artesunate is shown in Formula 2.
  • Artemether (ART) is a methyl ether derivative of Artemisinin with a molecular formula of C 16 H 26 O 5 and a molecular weight of 298.38.
  • the chemical structure of artemether is shown in Formula 3.
  • dihydroartemisinin has the advantages of high-efficiency antimalarial, low toxicity, and rapid onset of action. At present, it has good effects on anti-tumor activity, anti-immunosuppression such as lupus erythematosus, and anti-parasites.
  • Artesunate is esterified on the basis of dihydroartemisinin to become a water-soluble derivative of Artemisia annua L., which has high bioavailability and good therapeutic effects in anti-inflammatory and anti-tumor fields.
  • Artemether has six times the antimalarial effect as its lead compound artemisinin, and is widely used in the preparation of antimalarial drugs with high safety and low toxic and side effects.
  • artemether has anti-inflammatory and anti-tumor effects, and can be distributed into the central nervous system through the blood-brain barrier.
  • Artemether has been clinically proven to have both water-soluble and fat-soluble characteristics, and its chemical properties are more stable than other derivatives.
  • artemisininin derivatives used in the treatment of epilepsy.
  • the present invention uses artemisinin derivatives to explore brain diseases, so as to broaden the clinical value of artemisinin derivatives in medical applications.
  • the inventors found through a series of studies that artemether and artesunate can effectively shorten the time of seizures and reduce the level of seizures; artemether can also improve the abnormal discharge of the hippocampal brain area caused by temporal lobe epilepsy, including reducing the time of epileptic discharge Cheng He increased the latency of seizures. It can be seen that artemisinin derivatives have good application prospects in the preparation of antiepileptic drugs, and can be used to prevent and treat epilepsy.
  • the purpose of the present invention is to provide a new application of artemisinin derivatives.
  • the present invention has found through experiments that artemisinin derivatives can reduce the time of seizures and reduce the level of seizures by inhibiting the abnormal discharge of brain epilepsy, thereby achieving resistance The role of epilepsy.
  • the invention provides the application of artemisinin derivatives in the preparation of antiepileptic drugs.
  • the artemisinin derivative includes artemether, artesunate or a pharmaceutically acceptable salt thereof.
  • the epilepsy is temporal lobe epilepsy.
  • the present invention has found through experiments that artemether and artesunate can play a good role in inhibiting brain epilepsy abnormal discharge, can effectively shorten the time of seizures, reduce the level of seizures, and have good antiepileptic effects.
  • the inventor found in the study that artemether and artesunate have a good antiepileptic effect when the dose is 50 mg / kg.
  • the present invention does not limit the effective dose of artemisinin derivatives in antiepileptic drugs. Its implementation is within the protection scope of the present invention.
  • the invention also provides an antiepileptic drug, which includes an effective amount of an artemisinin derivative and at least one pharmaceutically acceptable excipient.
  • an artemisinin derivative includes artemether, artesunate or a pharmaceutically acceptable salt thereof.
  • the antiepileptic drug is an oral preparation or an injection preparation; preferably, the oral preparation is selected from tablets, capsules, soft capsules, granules, suspensions, pills, pills, oral liquid preparations One of them; preferably, the tablet is an ordinary tablet, a dispersible tablet, an orally disintegrating tablet or a sustained-release tablet; preferably, the injection preparation is an injection solution or a powder injection.
  • the invention also provides an anti-temporal lobe epilepsy medicine, which includes an effective amount of an artemisinin derivative and at least one pharmaceutically acceptable auxiliary material.
  • the artemisinin derivative includes artemether, artesunate or a pharmaceutically acceptable salt thereof.
  • the anti-temporal lobe epilepsy drug is an oral preparation or an injection preparation; preferably, the oral preparation is selected from tablets, capsules, soft capsules, granules, suspensions, pills, pills, oral One of liquid formulations; preferably, the tablet is an ordinary tablet, a dispersible tablet, an orally disintegrating tablet, or a sustained-release tablet; preferably, the injection formulation is an injection solution or a powder injection.
  • artemisinin derivatives can effectively improve seizures, including 1) reducing the duration of epilepsy abnormalities in the hippocampal CA1 area and increasing the latency of epilepsy abnormalities, 2) Reduce the time of seizures, 3) Reduce the level of seizures. It shows that artemisinin derivatives have good application prospects in the field of antiepileptic drugs, especially for the prevention and treatment of temporal lobe epilepsy, reduce the damage of epilepsy to brain function, and have obvious curative effect, high safety and low price.
  • FIG. 1 is a study of the artemisinin derivatives dihydroartemisinin, artesunate, and artemether in inhibiting kainic acid (KA) -induced epilepsy in Example 1 of the present invention
  • FIG. A is Example 1 of the present invention Schematic diagram of the implementation of the experimental scheme
  • Figures B and C are the statistical results of the artemisinin derivative of Example 1 of the present invention reducing the time and grade of KA-induced seizures.
  • FIG. 2 is a concentration-dependent study of artemether inhibiting KA-induced epilepsy in Example 2 of the present invention.
  • Figure A is a schematic diagram of the implementation of the experimental scheme of Example 2 of the present invention;
  • Figures B and C are statistical results of different concentrations of artemether in inhibiting seizure time and grade of Example 2 of the present invention.
  • FIG. 3 shows that artemether in Example 3 of the present invention inhibits KA-induced epilepsy behavior and epilepsy EEG abnormalities.
  • Figure A is a schematic diagram of the implementation scheme of Example 3 of the present invention;
  • Figures B and C are the statistical results of artemether (50 mg / kg) of Example 3 of the present invention reducing the time and grade of seizures caused by KA (due to the Unmodeled animals did not exhibit epilepsy behavior and epilepsy EEG abnormalities, so data such as the seizure latency period could not be obtained, so panel B and panel C do not show the control group data).
  • Figure D is a representative example of artemether in Example 3 of the present invention inhibiting KA-induced epilepsy abnormal discharge in the hippocampal CA1 area of mice;
  • Figures E and F are the results of artemether in Example 3 of the present invention causing KA Statistical results of seizure abnormal discharge seizure duration and discharge latency in the hippocampal CA1 area of mice.
  • FIG. 4 shows that artemether in Example 4 of the present invention inhibits electrical ignition-induced epilepsy behavior and epileptic brain electrical abnormalities.
  • Figure A is a schematic diagram of the implementation of the experimental scheme of Example 4 of the present invention;
  • Figure B is a representative example of artemether (50 mg / kg) of Example 4 of the present invention inhibiting the epileptic abnormal discharge in the hippocampal CA1 area of the mouse caused by electrical ignition
  • Figure C is the statistical result of the artemether of Example 4 of the present invention inhibiting the level of seizures in mice caused by electrical ignition;
  • Figure D is the number of times the artemether of Example 4 of the present invention causes different levels of seizures caused by electrical ignition Statistical results;
  • Figure E is a statistical result of the number of electrical stimulations required by artemether in Example 4 of the present invention for the generalized seizures in mice caused by electrical ignition.
  • the present invention further illustrates that artemisinin derivatives can effectively control seizures through the following examples.
  • the dose of 50 mg / kg is used to study the antiepileptic effect of artemether and artesunate, which is only used to illustrate the technical effect of the present invention, not to limit the scope of protection of the present invention.
  • the methods used are conventional methods unless otherwise specified.
  • This example provides a new use of artemisinin derivatives.
  • the use of artemisinin derivatives is mainly detected by different artemisinin derivatives interfering with the effect of KA-induced epilepsy behavior.
  • SPF grade C57BL / 6 mice male, 8 weeks old, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd.
  • SPF-level animal center feeding the temperature of the feeding area is generally between 25-28 °C, the humidity is controlled between 40% -70%, the microcomputer controls the fluorescent lamp lighting system, and the light and dark are automatically alternated for 12h.
  • the animal center cleans regularly, replaces animal litter, adds feed, and can freely take in SPF-grade breeding-grade feed and drinking water.
  • Kainic acid (kainic acid, KA), purchased from Sigma-Aldrich (Shanghai, China); dihydroartemisinin, purchased from Maclean Biochemical Technology Co., Ltd. (Shanghai, China); artesunate, purchased from Maclean Biochemical Technology Co., Ltd. (Shanghai, China); Artemisinin (Art), purchased from Aladdin Biochemical Technology Co., Ltd. (Shanghai, China).
  • Methyl cellulose (Methylcellulose, MC), purchased from Sigma-Aldrich Company (Shanghai, China); NaCl, purchased from Sigma-Aldrich Company (Shanghai, China).
  • KA is injected intraperitoneally at a dose of 10 mg / kg (KA is prepared by dissolving 0.9% NaCl solution) to induce temporal lobe epilepsy in animals and establish an acute KA-induced epilepsy model.
  • KA + DHA and KA + AS intervention groups were intraperitoneally injected with corresponding artemisinin derivatives 1h before modeling, KA + Art intervention group was intraperitoneally injected Art 2h before modeling, model group (KA ) The same dose of MC is injected at the same time before modeling, and the specific model administration time is shown in Figure 1.
  • Seizure test method ( Figure 1A): use high-definition camera to record and analyze seizure time and seizure level in mice.
  • the level of seizures is based on the Racine rating standard: level 1 chewing exercise, that is, facial muscle twitching, including blinking, twitching, and rhythmic chewing; level 2, adding nod movement on the basis of level 1, that is, neck muscle twitching; level 3, On the basis of level 2, one side of the forelimb clonics was added; on the basis of level 3, the hind legs were standing and bilateral forelimb clonics were added; on level 5, the bilateral forelimb clonics were aggravated and the balance was lost.
  • level 1 chewing exercise that is, facial muscle twitching, including blinking, twitching, and rhythmic chewing
  • level 2 adding nod movement on the basis of level 1, that is, neck muscle twitching
  • level 3 On the basis of level 2, one side of the forelimb clonics was added; on the basis of
  • This embodiment provides a new application of artemether.
  • the use of artemether is mainly tested by examining the effect of different concentrations of artemether on the epilepsy behavior caused by KA.
  • This embodiment provides a new application of artemether.
  • the use of artemether is mainly tested by detecting the effect of artemether intervention on the epilepsy behavior and abnormal epilepsy caused by KA.
  • Drugs and main reagents (same as Example 1): the gas anesthetic agent isoflurane used when burying the electroencephalogram recording electrode was purchased from Ruiwo De Life Technology Co., Ltd. (Shenzhen, China).
  • Electroencephalogram recording electrode production 4 nickel-chromium alloy wires (# stablohm675, diameter 35 ⁇ m, CFW, USA) are arranged in parallel, soldered to a self-made circuit board by soldering, and a silver wire is welded at one end of the electrode to serve as a ground wire It was connected to one of the skull nails, and then the electrodes were wrapped with AB glue for insulation.
  • the four electrodes were fixed with polyethylene glycol with a molecular weight of 3350 (# P3640, Sigma-Aldrich, Shanghai, China).
  • Test method for seizures (Figure 3A): 1) EEG recording in hippocampal CA1 area: anesthetize the mouse with isoflurane, fix the skull with a stereotaxic apparatus, remove the skull hair with hair removal cream, and expose the skull; determine the hippocampus; CA1 coordinates (AP-1.7mm, ML 1mm, DV 1.2mm); fix three screws near the marked area with a skull drill, make four-channel electrodes buried in the mark, and fix them with dental cement after the electrodes are buried; the electrodes are buried
  • EEG was recorded using an in-vivo multi-channel neural signal acquisition system (Appollo, Bio-signal technologies, USA) (sampling rate 1kHz, low-pass filter 200Hz and high-pass filter 300Hz), and EEG analysis was performed using NeuroExplorer software (Nex Technologies) : Boston, MA, USA).
  • mice after each electrical stimulation was collected through a high-definition camera, and the seizure grades of each group after electrical stimulation were analyzed according to the Racine grade standard (same as Example 1).
  • Electrodes were recorded by implanting electrodes in the CA1 area of the hippocampus of the mouse and the seizure behavior after KA modeling was observed. At the same time, the Appollo neural signal acquisition system was used to record the EEG.
  • This embodiment provides a new application of artemether. Mainly to test the use of artemether by detecting the effect of artemether intervention on epilepsy abnormal discharge and epilepsy behavior caused by electrical ignition
  • Test method ( Figure 4A): 1) Hippocampal brain electrical stimulation and recording, electrical ignition stimulates the hippocampal CA3 area through the stimulator output current, and records the electrical signal in the CA1 area through the Appollo multi-channel signal acquisition system, recording each electrical stimulation EEG waveform.
  • Behavioural records are recorded at the same time as the electrical ignition, and the behavior of the mice after each electrical stimulation is collected through a high-definition camera, and the seizure levels of each group after electrical stimulation are analyzed according to the Racine rating standard (same as Examples 1 and 3) , And count the distribution of numbers of electrical seizures caused by electrical stimulation (Numbers of stimulation for stages distribution) and the number of electrical stimulation required to reach level 5 (Numbers of stimulation to 5 stages).
  • Ignite stimulation was recorded by implanting electrodes in the hippocampus of the mouse and recorded EEG and observed behaviors.
  • multi-channel neural signal acquisition system was used to record EEG.
  • artemether can significantly reduce the cause of electrical ignition Hippocampal CA1 epileptic EEG abnormalities ( Figure 4B)
  • synchronized behavioral analysis showed that 50mg / kg artemether significantly reduced the level of seizures and increased the number of electrical stimulations required to reach level 5 seizures (Figure 4C, E).
  • the present invention uses artemisinin derivatives for antiepileptic effects for the first time, and the results show that artemisinin derivatives can effectively control the onset of epilepsy, suppress brain epilepsy abnormalities in brain, and in the development of new antiepileptic drugs Has a good prospect.

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Abstract

La présente invention concerne une nouvelle application de dérivés d'artémisinine, en particulier une application de dérivés d'artémisinine dans la préparation d'un médicament anti-épileptique ; les dérivés d'artémisinine sont de préférence l'artéméther, l'artésunate ou des sels pharmacologiquement acceptables de ces derniers, et la forme d'épilepsie est de préférence l'épilepsie du lobe temporal. Après une recherche approfondie, l'inventeur a découvert que l'artéméther ainsi que l'artésunate permettent de lutter efficacement contre des crises d'épilepsie et d'inhiber une décharge électrique anormale dans le cerveau qui provoque l'épilepsie. La présente invention montre que l'artéméther et l'artésunate ont de bonnes perspectives d'application dans le domaine des médicaments anti-épileptiques, en particulier pour la prévention et le traitement d'une lésion de la fonction cérébrale d'un organisme provoquée par l'épilepsie ; pendant ce temps, l'efficacité des dérivés est considérable, la sécurité est élevée, le prix est faible, et le fardeau financier pesant sur les patients peut être réduit.
PCT/CN2018/121596 2018-11-02 2018-12-17 Application de dérivés d'artémisinine dans la préparation d'un médicament anti-épileptique WO2020087685A1 (fr)

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CN201811306343.5A CN109331012A (zh) 2018-11-02 2018-11-02 青蒿素衍生物在制备抗癫痫药物中的应用

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009155379A2 (fr) * 2008-06-17 2009-12-23 Hhv-6 Foundation Artémisinine et dérivés de celle-ci en tant qu’antiviraux
CN106459079A (zh) * 2014-04-11 2017-02-22 分子医学研究中心责任有限公司 青蒿素化合物及桥蛋白激动剂的医疗用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009155379A2 (fr) * 2008-06-17 2009-12-23 Hhv-6 Foundation Artémisinine et dérivés de celle-ci en tant qu’antiviraux
CN106459079A (zh) * 2014-04-11 2017-02-22 分子医学研究中心责任有限公司 青蒿素化合物及桥蛋白激动剂的医疗用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HE, XIN ET AL.: "The Protective Effects of Artemisinin on Penicillin Sodium-Induced Epileptic Seizures in Mice.", LATIN AMERICAN JOURNAL OF PHARMACY, vol. 35, no. 1, 31 December 2016 (2016-12-31), pages 1241 - 1247, XP009520925, ISSN: 0326-2383 *
ORIAIFO ET AL.: "Prevention of epilepsy by low-dose artesunate + esomeprazole-furosemide sequential therapy", WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES., vol. 6, no. 8, 31 December 2017 (2017-12-31), XP009520943, ISSN: 2278-4357 *

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