WO2005102314A1 - Utilisation d'homologues de butylphthalide dans la preparation d'un medicament destine au traitement et a la prevention de l'ischemie cerebrale - Google Patents

Utilisation d'homologues de butylphthalide dans la preparation d'un medicament destine au traitement et a la prevention de l'ischemie cerebrale Download PDF

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WO2005102314A1
WO2005102314A1 PCT/CN2005/000556 CN2005000556W WO2005102314A1 WO 2005102314 A1 WO2005102314 A1 WO 2005102314A1 CN 2005000556 W CN2005000556 W CN 2005000556W WO 2005102314 A1 WO2005102314 A1 WO 2005102314A1
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butylphthalide
group
cerebral
hydroxy
rats
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PCT/CN2005/000556
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English (en)
Chinese (zh)
Inventor
Zhentao Liu
Hongwu Zhang
Dongmin Shen
Xiaolong Feng
Rongduan Wang
Jingguo Sun
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Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology(Shijiazhuang) Co., Ltd.
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Publication of WO2005102314A1 publication Critical patent/WO2005102314A1/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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to butylphthalide homologues, specifically 3- (3'-hydroxy) butylphthalide,
  • Butylphthalide also known as celeryme, was originally found in celery seeds, and its pharmacodynamic characteristics covered many aspects: 1. Improving ischemic brain energy metabolism; 2. Significantly reducing ischemic cerebral infarction in rats Area, improve neurological deficits; 3. improve cerebral edema caused by ischemia; 4. significantly improve local cerebral blood flow and pia mater circulation in the ischemic area; 5. significantly improve memory impairment caused by ischemia. The side effects are small.
  • Chinese Patent Application No. 93117148.2 the application of apigenin in the preparation of a medicament for preventing and treating diseases caused by cerebral ischemia in mammals or humans is disclosed.
  • the object of the present invention is to provide new applications of butylphthalide homologues 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide, so that it can be used in the development of future drugs as A new active ingredient is used in pharmaceutical preparations.
  • 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide, which are homologs of butylphthalide have the following pharmacological effects:
  • the inventors of the present application provided the following uses of 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide, which are homologs of butylphthalide.
  • the present invention provides butylphthalide homologs 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide in preparations for preventing and treating cerebral ischemia. Use in disease-causing drugs.
  • the disease caused by cerebral ischemia is selected from neurological symptoms caused by cerebral ischemia, memory disorders caused by cerebral ischemia, cerebral edema caused by cerebral ischemia, stroke caused by cerebral ischemia, and brain deficiency Impaired energy metabolism caused by blood, cerebral infarction caused by cerebral ischemia and loss of nerve function
  • the present invention provides butylphthalide homologues 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide in preparation for improving cerebral ischemic brain Use of blood flow in medicine.
  • the present invention provides butylphthalide homologs 3- (3'-hydroxy) butylphthalide, 3-hydroxy-3-butylphthalide in the preparation of anti-platelet aggregation and antithrombotic Use in medicine.
  • the present invention provides butylphthalide homologs 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide in the preparation of a medicament for treating and preventing dementia. Use.
  • the beneficial effect of the present invention is to clarify the therapeutic effect of butylphthalide homologues 3- (3'-hydroxy) butylphthalide and 3-hydroxy-3-butylphthalide on diseases caused by cerebral ischemia. detailed description
  • Example 1 Effects of M1 and ⁇ on neurological symptoms caused by traumatic brain injury in rats Experimental animals: Male wistar rats
  • Neurobehavioral score Behavioral observation was performed 24 hours after ischemia. Lift the rat's tail about 1 foot away from the ground and observe the condition of the two forelimbs; push the rat's shoulders and observe whether there is a difference in resistance between the two sides; place the rat on the ground and observe its walking. Scoring according to the following criteria: 0 points: Both forelimbs are strong and symmetrically extend to the ground. Both shoulders have a resistance of 4 and the walking is normal.
  • mice The higher the score, the more severe the animal's behavioral disorder.
  • Experimental grouping operation group (solvent control), group A (MI 20mg / kg), group B (MI 40mg / kg), group C (MI 80mg / kg), group D (MI II 20mg / kg), group E ( Mll40mg / kg), F group (Mll80mg / kg), G is MK801 O.lmg / kg group (injection), the other groups were administered orally.
  • the rats in the blank group had no abnormal behavior, with a neurobehavioral score of 0. Most of the animals in the solvent control group had a neurological score of 2 and showed contralateral forelimb internal rotation, and lateral compression of the contralateral extensor muscles weakened. . A small number of animals developed contralateral circle symptoms, which were rated as 3 points. Individual animals had mild symptoms and only showed contralateral forelimb internal rotation, with a score of 1; or severe symptoms, lack of autonomous activity, and scored 4 points. The mean nerve score in the solvent control group was 2.6 ⁇ 0.3.
  • Example 2 Effects of MI and Mil on memory impairment caused by ischemia Experimental equipment: Shuttle box, the same as in Example 1
  • Grouping and administration There are 8 groups, model group, sham operation group, group A (Ml 15mg / kg), group B (MI 30mg / kg), group C (Ml 60mg / kg), group D ( MlI 15 mg / kg), group E (Mll 30 mg / kg), and group F (MlI 60 mg / kg). Postoperative The drug was administered orally at 15 minutes, and the change of the latency of the active and passive avoidance responses to the rats was observed after 24 hours.
  • Rats were ligated with the right middle cerebral artery to cause cerebral edema. After 15 minutes, Ml and Mil (20, 40, 80 mg / kg) were orally administered, and they were sacrificed for 24 hours. The brain, called the left and right hemisphere wet weight. After baking at 100 ° C for 24 hours, the dry weight was measured, and the brain tissue water weight was calculated by the wet and dry method. The tissue was digested for 4 hours, the pH value was adjusted with HCI, and the ion-selective electrode was connected to an oxygen tissue analyzer to measure the Na + K + concentration in the brain tissue.
  • Table 2 Effects of Ml and ⁇ on brain water content in middle cerebral artery ligated ( ⁇ s) group Brain water content Na + content (micromolecule K + content (micromolecule /
  • M l and M il can significantly reduce cerebral edema caused by ischemia.
  • 6-week-old spontaneously hypertensive rats were divided into 7 groups of 10 rats each, and fed daily with 0.8-0.9 g of salt daily from the 6th week of age, and gradually increased to 1.2-1.3 g per day thereafter, starting from the 8th week Oral administration of Ml and Mil (12.5, 25, 50mg / kg / d) and nimodipine (37mg / kg / d) were started, and 3 weeks after the onset of stroke, the nerve loss score and the time of death were recorded.
  • the experimental group was divided into 8 groups: model group, positive drug group (nimodipine 37mg / kg / d), group A (MI 12.5mg / kg / d), group B (MI 25mg / kg / d), and group C (MI 50mg / kg / d), group D (MII 12.5mg / kg / d), group E (MII 25mg / kg / d), and group F (MII 50mg / kg / d).
  • mice MI and M II injections formulated with Tween 80 emulsion
  • Experimental method 10-22 g of Kunming mice were divided into 8 groups, 10 mice in each group, and Ml and M ⁇ (25, 50, 100 mg / kg / d) were administered orally as a blank control group, and phenobarbital sodium (225 mg / kg ip) 30 minutes after administration, decapitation to homogenization time of 15 seconds was used as cerebral ischemic time. Centrifugal extraction was performed according to the Folbergrova method and ATP, creatine phosphate (PCr) and lactic acid (LA) contents were measured by enzymatic method.
  • PCr creatine phosphate
  • LA lactic acid
  • Experimental grouping divided into 8 groups, blank control group, positive drug group (phenobarbital sodium 225mg / kg, ip), group A (25mg / kg / d), group B (50mg / kg / d), C Group (100 mg / kg / d D 25 mg / kg / d :), £ group (50 mg / kg / d), F 100 mg / kg / d)
  • Experimental results See Table 3. Compared with the blank control group, the ip-positive control group showed an increase in ATP and PCr and a decrease in lactic acid content, indicating that this method is reliable.
  • Tissue gas analyzer (Diamond Electro-Tech chemical microsensor 1231): manufactured by Diamond General, USA
  • Two-channel physiological recorder produced by Chengdu Instrument Factory
  • M I and Mil (15, 30, 60 mg / kg) and a solvent were orally administered to normal rats, and changes in cerebral blood flow at different times after the administration were measured.
  • Rats were subjected to cerebral arterial ligation according to the Tamura method, and were orally administered at 10 minutes after operation. They were divided into 8 groups, a sham operation group, a solvent control group, and a M1 and M ⁇ (15, 30, 60 mg / kg) group.
  • Ml can increase cerebral blood flow and improve brain blood supply without substantially affecting blood pressure.
  • the Ml group can significantly increase the local blood flow in the cerebral arteries and block the lateral striatum.
  • the effect of the ⁇ (60mg / kg) group was more obvious, compared with the blank control group, PO.05, and there was no significant effect in the other drug groups. It shows that Ml and Mil can not only increase the cerebral blood flow in normal rats, but also increase the cerebral blood flow in the ischemic area. Ml has a better effect.
  • Example 7 Effects of MI and Mil on Cerebral Infarction Area and Neural Function Loss in Focal Cerebral Ischemia Rats Experimental animal: same as in Example 1
  • Rats were subjected to brain movement and permanent ligation according to the Tamura method, and were orally administered 10 min after surgery. They were divided into 8 groups, a sham operation group, a solvent control group, and MI and M (15, 30, 60 mg / kg) group.
  • Example 8 M I and Mil antiplatelet aggregation and antithrombotic effect
  • Rats were anesthetized with 10% chloral hydrate (30mg / kg), blood was collected from the carotid arteries, and platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared according to conventional methods. Refer to the Bom's method, and take PKK 200 ⁇ 1, and add the drugs separately.
  • the two concentration curves for M l and M ⁇ range from 1, 3, 10, 30, and 100 ⁇ M. Place it on a platelet aggregator and pre-warm it at 37 ° C for 5 minutes. Then add ADP as the final concentration to 5 ⁇ M, and determine the maximum aggregation rate of the platelet after 5 minutes.
  • the rats were randomly divided into 15 groups of 3 animals each, which were the solvent control group and M l And Mll (50mg / kgp.o.) Blood was taken at different times (30, 45, 60, 90, 120, 180, 240min). Animals in each group were anesthetized with chloral hydrate (30mg / kg) at the corresponding time points after administration, and blood was collected from the carotid artery.
  • Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared according to conventional methods, with reference to Bom's Method: Take 200 ⁇ 1 of PKP, place it on a platelet aggregation meter, and pre-incubate at 37 ° C for 5 minutes, then add the inducer ADP (5 mol / l), and determine the maximum platelet aggregation rate after adding the attractant for 5 minutes.
  • the rats were divided into 17 groups of 10 animals each, which were the control group, the aspirin group, the M1 and M ⁇ (3, 10, 30, 100mg / kg po single administration) group, and the celopidine (100mg / kg continuous administration for 3 days) group.
  • Blood was taken from the carotid artery after anesthesia with chloral hydrate (30mg / kg) 2h after the last administration, and platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared according to the conventional method.
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • Rats were randomly divided into 10 groups with 10 animals in each group. Fasting the night before the experiment. Oral Asp, MI and ⁇ (dose of 3, 10, 30, 100 mg / kg for each drug) and the same volume of vegetable oil. Two hours after the administration, the rats were anesthetized with 30 mg / kgip sodium pentobarbital, fixed in the supine position, and the right common carotid artery and the left external jugular vein were separated. Take a three-section polyethylene tube with an inner diameter of 0.9 mm and a length of about 12 cm (built-in 6 cm long silk thread, and the silk thread is weighed). The tube is filled with normal saline and connects the right common carotid artery and the left external jugular vein.
  • collagen 1000 g / kg including epinephrine 8
  • ⁇ g / kg the injection was completed within 20 seconds, and the mortality of the animals was observed within 5 minutes.
  • the protective effect of the drug was represented by the decrease in the ratio of the number of surviving animals to the number of experimental animals.
  • mice Male Kunming mice were fasted before the experiment. The mice were divided into 8 groups, a solvent control group, an Aspl00 mg / kg, MI and Mil (10, 30, 100 mg / kg) group. 2 hours after gavage, cut off the rat tail 5iran, start timing, and gently touch the sore surface of rat tail bleeding with qualitative filter paper every 30 sec, so that blood is printed on the filter paper, and printed once every 30 sec until there is no blood on the filter paper. Time to start bleeding to no blood.
  • Ml and MII 3, 10, 30, 100 mg / kg All inhibited collagen, ADP, and AA-induced platelet aggregation in a dose-dependent manner.
  • Ml had a stronger effect, while Mil had a weaker effect.
  • the effect on ADP-induced platelet aggregation was similar to that of seclopidine for three days.
  • M l and MII can inhibit experimental thrombosis in a dose-dependent manner, all in a dose-effect relationship.
  • the inhibitory rates of M l (3, 10, 30, 100 mg / kg p.o) on thrombosis were 13%, 25%, 44%, and 45%, respectively.
  • the inhibition rates of Asp (3, 10, 30, 100 mg / kg p.o) were 4%, 27%, 44%, and 48%, respectively.
  • the results showed that the antithrombotic effect of M I was slightly weaker than that of aspirin at the same dose, and Mil had antithrombotic effect only at high doses (30, 100 mg / kg p.o).
  • M l (10, 30, 100 mg / kg) dose-dependently increased bleeding time in mice.
  • M l had a stronger effect than aspirin at the same dose, and ML only had this effect at large doses (100 mg / kg p.o).
  • 2-VO model establishment Male Wistar rats, 10 weeks old, weighing about 280 grams, anesthetized with sodium pentobarbital, and bilateral common carotid artery ligation.
  • the sham operation group underwent the same operation except that the common carotid artery was not ligated.
  • mice There are 8 groups in total, the same as in Example 2. Dosing started 10 days after surgery, A water maze experiment was performed on days 29-33, and a dark avoidance experiment was performed on days 34-35. Animals were sacrificed on day 36. In behavioral experiments, they were administered 40 minutes before the experiment.

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Abstract

L'invention concerne l'utilisation d'homologues de butylphthalide dans la préparation d'un médicament destiné au traitement et à la prévention de l'ischémie cérébrale et la démence, de la thrombose résistante, ainsi que de l'agglutination des plaquettes. Ces homologues de butylphthalide correspondent à: 3-(3'-hydroxyl)butylphtalide et 3-hydroxyl-3-butylphthalide.
PCT/CN2005/000556 2004-04-23 2005-04-22 Utilisation d'homologues de butylphthalide dans la preparation d'un medicament destine au traitement et a la prevention de l'ischemie cerebrale WO2005102314A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011527290A (ja) * 2008-07-08 2011-10-27 インスティトゥート オブ マタリア メディカ，チャイニーズ アカデミー オブ メディカル サイエンシズ ２−（α−ヒドロキシ−ペンチル）安息香酸カリウムを用いたアルツハイマー病の予防と／またおよび／または治療においての役割への適用
US20140288027A1 (en) * 2011-10-13 2014-09-25 Shijiazhuang Yiling Pharmaceutical Co., Ltd Derivative of Butylphthalide and Preparation Method and Use Thereof
WO2016000265A1 (fr) * 2014-07-04 2016-01-07 长弘生物科技股份有限公司 Applications d'un composé phtalide
CN112794831A (zh) * 2021-04-06 2021-05-14 北京理工大学 3-(3′-羟基丁基)异苯并呋喃-1(3h)-酮衍生物及其组合物、制备方法和用途
CN113666895A (zh) * 2020-05-15 2021-11-19 华北制药集团新药研究开发有限责任公司 卤代2-苯并[c]呋喃酮类化合物及其应用

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CN102988349A (zh) * 2012-11-19 2013-03-27 何晓涛 Aphanamixoid A在制备抗血小板聚集药物中的应用
CN104546827B (zh) * 2013-10-09 2019-12-27 石药集团恩必普药业有限公司 丁基苯酞或其衍生物在制备治疗或预防糖尿病的药物中的应用
CN104546828B (zh) * 2013-10-09 2017-11-14 石药集团恩必普药业有限公司 丁基苯酞或其衍生物在制备治疗或预防糖尿病并发症的药物中的应用
CN105267207A (zh) * 2014-07-10 2016-01-27 米文君 一种药物组合物及其用途
CN105348088A (zh) * 2014-08-18 2016-02-24 米文君 一种新的化合物及其用途
CN105503584A (zh) * 2014-09-28 2016-04-20 米文君 一种新的化合物及其用途
CN105523918A (zh) * 2014-09-28 2016-04-27 米文君 一种新化合物及其用途
WO2021185356A1 (fr) 2020-03-20 2021-09-23 石药集团恩必普药业有限公司 Utilisation de butylphtalide et dérivé associé

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011527290A (ja) * 2008-07-08 2011-10-27 インスティトゥート オブ マタリア メディカ，チャイニーズ アカデミー オブ メディカル サイエンシズ ２−（α−ヒドロキシ−ペンチル）安息香酸カリウムを用いたアルツハイマー病の予防と／またおよび／または治療においての役割への適用
US20140288027A1 (en) * 2011-10-13 2014-09-25 Shijiazhuang Yiling Pharmaceutical Co., Ltd Derivative of Butylphthalide and Preparation Method and Use Thereof
JP2014528460A (ja) * 2011-10-13 2014-10-27 石家庄以嶺薬業股▲ふん▼有限公司 ブチルフタリドの誘導体、並びにその製造法及び使用
US9278087B2 (en) 2011-10-13 2016-03-08 Shijiazhuang Yiling Pharmaceutical Co., Ltd. Derivative of butylphthalide and preparation method and use thereof
WO2016000265A1 (fr) * 2014-07-04 2016-01-07 长弘生物科技股份有限公司 Applications d'un composé phtalide
CN113666895A (zh) * 2020-05-15 2021-11-19 华北制药集团新药研究开发有限责任公司 卤代2-苯并[c]呋喃酮类化合物及其应用
CN113666895B (zh) * 2020-05-15 2023-12-08 华北制药集团新药研究开发有限责任公司 卤代2-苯并[c]呋喃酮类化合物及其应用
CN112794831A (zh) * 2021-04-06 2021-05-14 北京理工大学 3-(3′-羟基丁基)异苯并呋喃-1(3h)-酮衍生物及其组合物、制备方法和用途

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