CN100435792C - Application of butylbenzene phthalein homolog in preparation of medicine for treating cerebral ischemia disease - Google Patents
Application of butylbenzene phthalein homolog in preparation of medicine for treating cerebral ischemia disease Download PDFInfo
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- CN100435792C CN100435792C CNB2004100366283A CN200410036628A CN100435792C CN 100435792 C CN100435792 C CN 100435792C CN B2004100366283 A CNB2004100366283 A CN B2004100366283A CN 200410036628 A CN200410036628 A CN 200410036628A CN 100435792 C CN100435792 C CN 100435792C
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 206010008118 cerebral infarction Diseases 0.000 title abstract description 34
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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
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- 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
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- 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
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- 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
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Abstract
The present invention relates to the application of a butyl benzene phthalein homologous compound to the preparation of medicines for preventing and treating cerebral ischemia diseases, resisting platelet aggregating, resisting thrombi and treating and preventing aphrenia. The butyl benzene phthalein homologous compound of the present invention is 3-(3'-hydroxyl group) butylphthalide or 3-hydroxyl group-3-butylphthalide.
Description
Technical field
The present invention relates to the application of butylphthalide class homologue in preparation prevention and treatment cerebral ischemia disease, antiplatelet aggregation and antithrombotic and treatment and the dull-witted medicine of prevention.
Background technology
Butylphthalide has another name called Butylphthalide, is found at first in the celery seed, and its pharmacodynamics characteristics have contained the effect of a lot of aspects: 1, can improve the ischemia brain energy metabolism; 2, obviously dwindle rat local cerebral ischemia cerebral infarct size, improve neurological deficit; 3, improve the cerebral edema that local cerebral ischemia causes; 4, to ischemic region local cerebral blood flow and the effect of having clear improvement of pia mater encephali microcirculation; 5, can significantly improve the dysmnesia that local cerebral ischemia causes.And toxic and side effects is less.In Chinese patent 93117148.2, the application of Butylphthalide in the medicine of the disease that preparation prevention and treatment mammal or human cerebral ischemia cause disclosed.In addition in Chinese patent 98125618.X, disclose left-handed butylphthalide the preparation antithrombotic form and the anti-platelet aggregation medicine in application, clearly illustrate that this product has the effect of regulating neurocyte arachidonic acid metabolic after NOS-NO-cGMP systemic-function and the cerebral ischemia.
Wang Chunhua studies show that (Wang Chunhua etc.: the research Acta Pharmaceutica Sinica 1997 of butylphthalide metabolite in rat, 32 (9): 641-646), butylphthalide mainly changes into two kinds of metabolite 3-(3 '-hydroxyl) butylphthalide and 3-hydroxyl-3-butylphthalide (following figure below) in vivo.The ratio of original shape and metabolite is about 9: 91 in urine, the ratio of metabolite and prototype medicine is about 56: 44 in the cerebral tissue, but the metabolite in the brain has only MI, there is not MII, the pharmacodynamic action of these two kinds of metabolite is still indeterminate at present, from the structure of above-mentioned two chemical compounds, they all belong to the homologue of butylphthalide class.
3-(3 '-hydroxyl) butylphthalide (Metabolite I, MI)
3-hydroxyl-3-butylphthalide (Metabolite II, MII)
Summary of the invention
The object of the present invention is to provide the new purposes of butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide, by zoopery, seek their pharmacological action, provide a kind of new pharmaceutical usage for clinical, make it in the exploitation of future drugs, be applied in the pharmaceutical preparation as a kind of new active component.Butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide have the effect of the following aspects:
1, obviously improves the nervous symptoms that rat causes cerebral ischemia to cause because of cerebral trauma;
2, improve the dysmnesia that rat causes because of cerebral ischemia;
3, alleviate the cerebral edema that rat cerebral ischemia causes;
4, reduce the apoplexy that rat causes because of cerebral ischemia;
5, improve the energy metabolism that rat causes because of cerebral ischemia;
6, increase the ischemic region cerebral blood flow;
7, reduce local cerebral ischemia rat cerebral infarction area and alleviate the neurological deficit symptom;
8, antiplatelet aggregation and antithrombotic;
9, prevention and treatment are dull-witted.
The inventor on above-mentioned zoopery basis, has finished goal of the invention of the present invention just.
The present invention relates to butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, the purposes of 3-hydroxyl-3-butylphthalide in the medicine of preparation treatment mammal or the human disease that causes because of cerebral ischemia.
The present invention is specifically related to butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause the nervous symptoms that cerebral ischemia causes because of cerebral trauma in the preparation treatment medicinal usage.
The present invention is specifically related to the amnemonic medicinal usage that butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause because of cerebral ischemia in the preparation treatment.
The present invention is specifically related to the medicinal usage of the cerebral edema that butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause because of cerebral ischemia in the preparation treatment.
The present invention is specifically related to the medicinal usage of the apoplexy that butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause because of cerebral ischemia in the preparation treatment.
The present invention is specifically related to the medicinal usage of the energy metabolism that butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause because of cerebral ischemia in the preparation treatment.
The invention still further relates to the medicinal usage of butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide preparation treatment and prevention cerebrum ischemia district cerebral blood flow.
The invention still further relates to butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, cerebral infarction that the 3-hydroxyl-3-butylphthalide preparation treatment local cerebral ischemia causes and the medicinal usage of neurological deficit.
The invention still further relates to butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide prepares antiplatelet aggregation and antithrombotic medicinal usage.
The invention still further relates to butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide preparation treatment and the dull-witted medicinal usage of prevention.
Beneficial effect of the present invention has been clearly the treatment of diseases effect that butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide, 3-hydroxyl-3-butylphthalide cause cerebral ischemia.
The specific embodiment
For the present invention is described better, below with reference to animal experimental data explanation content of the present invention, wherein butylphthalide class homologue 3-(3 '-hydroxyl) butylphthalide abbreviates MI as, and 3-hydroxyl-3-butylphthalide abbreviates MII as.
Embodiment 1, MI and MII are to the influence of the nervous symptoms that causes because of the rat brain wound
Laboratory animal: male wistar rat
Experimental technique: the cone-shaped metal object with heavy 220g freely falls from the 30cm eminence, bump rats with left coronal suture rear side parietal bone, cause the rat brain wound, oral administration after 5 minutes: MI and MII (20,40,80mg/kg), marking evaluation behavior changes after 24 hours.
Experimental result: the nervous symptoms that rat causes with cerebral ischemia because of cerebral trauma, behind the oral administration, compare the remarkable nervous symptoms that improves that MI group can dose dependent with solvent control, the high dose group effect is more obvious among the MII, compare P＜0.05 with the blank group, show that two kinds of metabolite MI of butylphthalide and MII cause cerebral ischemia to cerebral trauma and the nervous symptoms that causes has the improvement effect.
The amnemonic influence that embodiment 2, MI and MII cause local cerebral ischemia
Experimental apparatus: shuttle box, other are with embodiment 1
Laboratory animal is with embodiment 1
Experimental technique:
(1) rat is carried out the acquired training of learning and memory:
(2) cerebral arteries ligation operation: according to the Tamura method rat is implemented the cerebral arteries ligation operation, after 24 hours, the experiment of replication learning and memory in rats, method is with (1).
(3) grouping and administration: be divided into 9 groups, normal group, sham operated rats, ischemic control group, MI and MII (15,30,60mg/kg) group.15 minutes oral administrations of postoperative are observed medicine to rat active and the preclinical variation of passive avoidance response after 24 hours.
Experimental result: the ischemic control group is compared with normal group, and the obvious loss of memory of rat is initiatively avoided number of times and reduced, and illustrates to have produced dysmnesia.Compare with the solvent control group, MI and MII group is initiatively avoided time number average obviously to be increased, and shows that MI and MII have to improve the amnemonic effect that local cerebral ischemia causes.
Embodiment 3, MI and MII are to the effect of rat brain artery ligation cerebral edema
Laboratory animal is with embodiment 1
Experimental technique: rat is implemented right side middle cerebral artery ligation, cause cerebral edema, after 15 minutes, oral MI and MII (20,40,80mg/kg) put to death in 24 hours, got forebrain, claimed left and right brain hemisphere weight in wet base.Bake for 100 ℃ and claim dry weight after 24 hours, the dried wet method calculating of usefulness brain water weight.To organize nitrated 4 hours, transfer pH value, be connected on the oxygen fabric analysis instrument, survey cerebral tissue Na with ion-selective electrode with HCI
+, K
+Concentration.
Experimental result: MI group reduces the brain water yield and Na
+Content increases K+ content highly significant, and dose-effect relationship is arranged; The high dose group effect is more obvious among the MII, compares P＜0.05 with the blank group.Illustrate that MI and MII can obviously alleviate the cerebral edema that local cerebral ischemia causes.
Embodiment 4, MI and MII are to the effect of spontaneous hypertensive rat apoplexy
Laboratory animal: 6 the week age spontaneous hypertensive rat
Experimental technique: 6 the week age spontaneous hypertensive rat, be divided into 7 groups, every group 10, from the 6th the week every day in age feeding salt 0.8-0.9g, progressively increase to 1.2-1.3g every day later on, rose in the 8th week and begin respectively oral MI and MII (12.5,25,50mg/kg/d), nimodipine (37mg/kg/d), take place 3 weeks of back to end record neural disappearance mark and death time to apoplexy.
Experimental result: compare with the solvent control group, MI and MII can obviously delay the time of cerebral seizure, show the effect that it has the prevention of brain apopiecticus insultus; But survival rate behind the remarkable increase cerebral seizure of MI dose dependent and the neural disappearance effect of improvement show that it has therapeutical effect to the apoplexy that spontaneously hypertensive causes simultaneously.Prompting MI causes that to serious hypertension cerebral apoplexy patient has prevention and therapeutical effect, and MII causes that to serious hypertension cerebral apoplexy patient has preventive effect, and therapeutical effect is not obvious.
The influence of the global brain ischemia brain energy metabolism that embodiment 5, MI and MII cause mice broken end
Laboratory animal is with embodiment 1
The experiment medicine: injection MI and MII prepare Emulsion with Tween 80
Experimental technique: get Kunming mouse 10-22g and be divided into two groups, every group 10, oral MI and MII (25,50,100mg/kg/d), sodium phenobarbital (225mg/kg ip), group of solvents, breaked end in 30 minutes after the administration to 15 seconds homogenate time as ischemic time, carry out centrifugal extraction and measure lactic acid, ATP and PCr content according to the Folbergrova method with the zymetology method.
Experimental result: ischemic control group brain lactic acid content rises, and ATP and PCr descend, ip positive control drug group, and lactic acid content obviously descends, and ATP and PCr rise.Behind the oral MI, lactic acid content obviously descends, and ATP and PCr rise, and with matched group the difference of highly significant is arranged relatively; The MII group does not have obviously effect.This results suggest MI has the effect that improves brain energy metabolism.
Embodiment 6, MI and MII are to the influence of local cerebral blood flow
Experimental apparatus: SXP-operating microscope, 62TZ-V type high frequency electric knife
Laboratory animal: male wistar rat
Stereotaxic instrument: Shanghai Jiang Wan I type C
Organize gas analyser (Diamond Electro-Tech chemical microsensor1231): U.S. Diamond General company produces
Two road physiology monitors: Chengdu Instruement Factory produces
Experimental technique:
(1) normal rat oral administration MI and MII (15,30,60mg/kg), solvent measure that the cerebral blood flow of different time changes after the administration.
(2) according to the Tamura method rat is implemented the cerebral arteries ligation operation, postoperative 10min oral administration is divided into 8 groups, sham operated rats, solvent control group, MI and MII (15,30,60mg/kg) group.
Experimental result: normal rat give MI after 30 minutes cerebral blood flow obviously increase, 60 minutes cerebral blood flows still keep higher level behind the medicine, prolongation in time later on, increasing degree is by ashamed reduction, blood pressure there is not influence, as seen MI can be under the situation that does not influence blood pressure substantially cerebral blood flow increasing, improve cerebral blood supply.Artery ligation operation back MI group can significantly increase the striatal regional flow of middle cerebral artery blocking-up side, compares with the solvent control group, and there were significant differences, and dose-effect relationship is arranged.The effect of MII (60mg/kg) group is more obvious, compares P＜0.05 with the blank group, and other each medication group does not have obvious effect.Show that MI and MII can not only increase the normal rat cerebral blood flow, also can increase the ischemic region cerebral blood flow, the effect of MI is better.
Embodiment 7, MI and MII are to the influence of local rats with cerebral ischemia cerebral infarct size and neurological deficit
Laboratory animal is with embodiment 1
Experimental technique:
According to the Tamura method rat is implemented the cerebral arteries ligation operation, postoperative 10min oral administration is divided into 8 groups, sham operated rats, solvent control group, MI and MII (15,30,60mg/kg) group.
Experimental result: the nervous symptoms that the rat local cerebral ischemia causes, behind the oral administration, compare the remarkable nervous symptoms that improves that MI group can dose dependent with operating comparison, reduce infarct size, the high dose group effect is more obvious among the MII, compare P＜0.05 with the blank group, show two kinds of metabolite MI of butylphthalide and the nervous symptoms effect of having clear improvement that MII causes local cerebral ischemia.
Embodiment 8, MI and MII antiplatelet aggregation and anti thrombotic action
Experimental drug and instrument: aspirin (aspirin, Asp), adenosine diphosphate (ADP), collagen (collagen, Coll), arachidonic acid (arachidonic acid, AA).
Platelet aggregation instrument (PAT-4A type MEGURO-KU TOKYO JAPAN)
Animal
Male Wistar rat, body weight 280-320g; Male mice in kunming, body weight 22-26g.
(1) rats in vitro platelet aggregation test
Rat 10% chloral hydrate (30mg/kg) anesthesia, carotid artery is got blood, prepares platelet rich plasma (PRP) and platelet poor plasma (PPP) according to a conventional method, with reference to the BornShi method, get PRP200ul, add medicine respectively, two concentration curve scopes of MI and MII are 1,3,10,30,100 μ M.Place on the platelet aggregation instrument, 37 ℃ temperature is after 5 minutes in advance, and adding lures poly-agent ADP, and making its final concentration is 5uM, is determined at and lures the platelet maximum agglutination rate of poly-agent adding after 5 minutes.
(2) MI and MII are to the time-effect relationship of rat at the body platelet aggregation
Rat is divided into 15 groups at random, every group of 3 animals, be respectively solvent control group and MI and MII (50mg/kg p.o.) different time (30,45,60,90,120,180,240min) get blood.Every treated animal respectively at administration after corresponding time point after chloral hydrate (30mg/kg) anesthesia, get blood in carotid artery, prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) according to a conventional method, with reference to the BornShi method, get PRP200ul, place on the platelet aggregation instrument, 37 ℃ of pre-temperature are after 5 minutes, add derivant ADP (5 μ mol/l) respectively, be determined at and lure the platelet maximum agglutination rate of poly-agent adding after 5 minutes.
(3) rat is at the body platelet aggregation test
Rat is divided into 17 groups, and every group of each 10 animal are respectively matched group, aspirin group, MI and MII (3,10,30,100mg/kg p.o single-dose) group and plug chloropyridine (100mg/kg successive administration 3 days) group.After chloral hydrate (30mg/kg) anesthesia, get blood in 2h after the last administration in carotid artery, prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) according to a conventional method, with reference to the BormShi method, get PRP200ul, place on the platelet aggregation instrument, 37 ℃ of pre-temperature are after 5 minutes, add respectively that to lure poly-agent ADP, collagen, AA to make its final concentration be 5umol/l, 100ul/ml, 0.5mmol/L is determined at and lures the platelet maximum agglutination rate of poly-agent adding after 5 minutes.
(4) rat arteriovenous loop experimental thrombosis forms model
Rat is divided into 10 groups at random, every group of 10 animals.Experiment fasting in eve.Oral Asp, (dosage of every kind of medicine is respectively 3,10,30,100mg/kg) with the vegetable oil of volume for MI and MII.Behind the administration 2h, rat is anaesthetized with pentobarbital sodium 30mg/kg ip, dorsal position is fixed, and separates right common carotid artery and left external jugular vein.Get internal diameter 0.9mm, be about in three sections polyethylene tubes (silk thread that built-in 6cm is long, silk thread is weighed) pipe of 12cm and be full of normal saline, connect right common carotid artery and left external jugular vein.Open bulldog clamp, blood flow in the polyethylene tube from right common carotid artery, returns left external jugular vein, middle Herba Clinopodii behind the open blood flow 15min.Take out silk thread rapidly and weigh, the silk thread weight in wet base deducts former silk thread dry weight, is thrombosed weight in wet base.
(5) the inductive mouse lung thrombotic model of collagen and epinephrine
Male mice in kunming, experiment fasting in eve.MI and MII; (dosage of every kind of medicine is respectively 30 to Asp; 100mg/kg) and with the vegetable oil of volume give mouse stomach; after the administration 2 hours; tail vein injection collagen 1000 μ g/kg (containing epinephrine 80 μ g/kg); be injected in 20 seconds and finish, observe the mortality rate of animal in the 5min, count the protective effect that ratio reduces the expression medicine with surviving animals number and laboratory animal.
(6) mice bleeding time experiment
Fasting before the male mice in kunming experiment.Mice is divided into 8 groups, the solvent control group, Asp100mg/kg, MI and MII (10,30,100mg/kg) group.Irritated behind the stomach 2 hours, the Mus tail is cut 5mm, pick up counting, the skin ulcer face that every 30sec is hemorrhage with the Mus tail contacts gently with qualitative filter paper, makes bloodstain on filter paper, and 30sec print once, till not having bloodstain on the filter paper, writes down and begins the hemorrhage time that arrives no bloodstain.
Experimental result:
1.MI and MII is to the influence of rats in vitro platelet aggregation
MI and MII P (1～100 μ M) have obvious inhibitory action to platelet aggregation.
2. left-handed butylphthalide is to the time-effect relationship of rat in the influence of body platelet aggregation
The result shows, MI and MII 50mg/kg are oral, the effect of anticoagulant prolongs in time and strengthens gradually, equal peakings about 2 hours, suppression ratio reaches about 50%, after recover gradually, so the 2 little time points after the administration of body experimental selection of mensuration MI and MII anticoagulant are got blood.
3.MI and MII is to the influence of rat at the body platelet aggregation
With the MI of concentration and MII (3,10,30,100mg/kg) inhibition Coll is arranged all, ADP, the effect of the inductive platelet aggregation of AA, and be dose-dependence, the MI effect is stronger, and a little less than the MII effect.MI is to Coll, and the inhibitory action of the inductive platelet aggregation of ADP is better than the Aspirin with dosage, and inductive platelet aggregation effect is weaker than Asp to AA.Three days administration results are similar to inductive platelet aggregation effect of ADP and plug chloropyridine.
4.MI and MII is to the influence of rat arteriovenous loop experimental thrombosis formation
The inhibition experimental thrombosis of MI and MII (3,10,30,100mg/kg p.o) energy dose dependent forms, and all is dose-effect relationship.MI (3,10,30,100mg/kg p.o) is respectively 13%, 25% to thrombotic suppression ratio, 44%, 45%.The suppression ratio of Asp (3,10,30,100mg/kg p.o) is respectively 4%, 27%, 44%, 48%.The result shows that the thromboembolism preventing effect of MI is weaker than isodose Aspirin slightly, and MII only just has the thromboembolism preventing effect in heavy dose of (30,100mg/kg p.o).
5.MI and MII is to collagen and the thrombotic influence of the inductive mouse lung of epinephrine
In the experiment of the inductive mouse lung thromboembolism of tail vein injection collagen and epinephrine, the survival rate of control group mice is 31%, and (100mg/kg p.o.) obviously increases the survival rate of pulmonary infarction mice, and the survival rate of mice is respectively 58% and 66% for MI and MII., action intensity and Aspirin (65%) and plug chloropyridine (70%) are suitable.
6. left-handed butylphthalide is to the influence in mice bleeding time
(10,30, in 100mg/kg) the increase mice bleeding time of dose dependent, the MI effect is better than with the Aspirin under the dosage MI, and MII only just has this effect at heavy dose of (100mg/kg p.o).
Embodiment 9, MI and MII are to the prevention and the therapeutical effect of dementia
(1) to the therapeutical effect of vascular dementia
Instrument: Morris water maze automatic monitoring instrument
The 2-VO modelling: male Wistar rat, 10 ages in week are about body weight 280 grams, with pentobarbital sodium anesthesia, bilateral ligation.Sham operated rats is accepted identical operation except that not ligation bilateral common carotid arteries.
Experiment grouping and design: be divided into 8 groups, sham operated rats, solvent control group, MI and MII (15,30,60mg/kg) group.Postoperative beginning in 10 days administration was carried out water maze laboratory in postoperative 29-33 days, kept away dark experiment in 34-35 days, and animal was put to death at the 36th day.In behavioristics's experiment, all in experiment administration in preceding 40 minutes.
Experimental result: behind the oral administration, MI and MII have obvious effect to nearly memory and the locus functional impairment of cerebral blood supply insufficiency rat.Prompting MI and MII have obvious treatment and preventive effect to vascular dementia.
Claims (1)
1, the purposes of 3-hydroxyl-3-butylphthalide in preparation antiplatelet aggregation and antithrombotic medicine.
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| CNB2004100366283A CN100435792C (en) | 2004-04-23 | 2004-04-23 | Application of butylbenzene phthalein homolog in preparation of medicine for treating cerebral ischemia disease |
| PCT/CN2005/000556 WO2005102314A1 (en) | 2004-04-23 | 2005-04-22 | The use of butylphthalide homologues in preparing the drug of preventing and treating cerebral ischemic |
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| CN101289438B (en) * | 2007-04-16 | 2012-04-18 | 山东绿叶天然药物研究开发有限公司 | 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses |
| AU2008359085A1 (en) * | 2008-07-08 | 2010-01-14 | Institute Of Mataria Medica , Chinese Academy Of Medical Sciences | The use of potassium 2-(alpha- hydroxypentyl) benzoate in the manufacture of medicaments for preventing and/or treating senile dementia |
| EP2767533B1 (en) * | 2011-10-13 | 2016-06-29 | Shijiazhuang Yiling Pharmaceutical Co., Ltd. | Derivative of butylphthalide and preparation method and use thereof |
| CN102988349A (en) * | 2012-11-19 | 2013-03-27 | 何晓涛 | Application of Aphanamixoid A for preparing platelet aggregation resistant medicine |
| CN104546827B (en) * | 2013-10-09 | 2019-12-27 | 石药集团恩必普药业有限公司 | Application of butylphthalide or derivatives thereof in preparing medicine for treating or preventing diabetes |
| CN104546828B (en) * | 2013-10-09 | 2017-11-14 | 石药集团恩必普药业有限公司 | Application of the butylphthalide or derivatives thereof in the medicine for treating or preventing diabetic complication is prepared |
| EP3165222B1 (en) * | 2014-07-04 | 2020-03-11 | Everfront Biotech Inc. | Use of phthalide compound |
| CN105267207A (en) * | 2014-07-10 | 2016-01-27 | 米文君 | Pharmaceutical composition and application thereof |
| CN105348088A (en) * | 2014-08-18 | 2016-02-24 | 米文君 | New compound and uses thereof |
| CN105523918A (en) * | 2014-09-28 | 2016-04-27 | 米文君 | Novel compounds and applications thereof |
| CN105503584A (en) * | 2014-09-28 | 2016-04-20 | 米文君 | Novel compound and applications thereof |
| WO2021185356A1 (en) | 2020-03-20 | 2021-09-23 | 石药集团恩必普药业有限公司 | Use of butylphthalide and derivative thereof |
| CN113666895B (en) * | 2020-05-15 | 2023-12-08 | 华北制药集团新药研究开发有限责任公司 | Halogenated 2-benzo [ c ] furanone compounds and application thereof |
| CN112794831B (en) * | 2021-04-06 | 2021-07-27 | 北京理工大学 | 3- (3' -hydroxybutyl) isobenzofuran-1 (3H) -one derivative, composition, preparation method and application thereof |
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