CN106946866A - A kind of medicine for preventing and treating cerebral apoplexy and preparation method thereof - Google Patents

Abstract

The invention relates to a medicine for preventing and treating stroke, especially ischemic stroke. The present invention studies and analyzes the structural characteristics of the coumarin derivative shown in formula I of the present invention, and studies its pharmacodynamic characteristics in rats, confirming that it has the ability to prevent and treat stroke, especially ischemic stroke role. In addition, the coumarin derivatives shown in the formula I of the present invention show good therapeutic activity in the mouse cerebral ischemia-reperfusion test, which can significantly reduce the behavioral score of the cerebral ischemia-reperfusion mice, and can relieve Damage the edema degree and water content of brain tissue, reduce the proportion of cerebral infarction, and it can be used to prevent and treat stroke, especially ischemic stroke.

Description

Medicament for preventing and treating stroke and preparation method thereof

technical field

The invention relates to the technical field of medicine, in particular to a medicine for preventing and treating stroke, especially ischemic stroke, and also relates to a preparation method of the medicine.

Background technique

Stroke is mainly divided into hemorrhagic stroke and ischemic stroke. The former mainly includes cerebral hemorrhage and subarachnoid hemorrhage; the latter mainly includes transient ischemic attack, cerebral thrombosis and cerebral embolism. Stroke is a common disease among middle-aged and elderly people, and its mortality rate is the first cause of death in our country. Among the survivors, about 75% of the patients still suffer from disabilities to varying degrees, and about 40% of the severely disabled patients have become a heavy burden on the family, society and the country. Therefore, it is extremely important to actively carry out primary prevention for people with risk factors to avoid the occurrence of stroke.

Ischemic stroke accounts for about 80% of all strokes, and its incidence increases with age. The occurrence of ischemic stroke is mainly due to the formation of cerebral embolism and local thrombus, which may be vascular narrowing and thromboembolism caused by atherosclerosis, or emboli from the heart flow to the brain with blood and cause cerebral infarction. Embolism; and vascular injury and vascular inflammation caused by various reasons are also one of the important reasons. Many reasons cause brain blood supply disorder, resulting in irreversible damage to damaged brain tissue, resulting in brain tissue ischemia, hypoxia and eventually necrosis, causing a series of neurological deficits and obstacles to patients. At present, according to the classification method of the most commonly used classification standard internationally recognized, TOAST classification system of ischemic stroke disease, ischemic stroke can be divided into 5 subtypes: large artery atherosclerotic type, cardiogenic embolism type, arteriolar occlusion type and unexplained type.

The current drug treatment of stroke aims to block the neuronal necrosis caused by ischemia, prolong the time of tolerable ischemia and the treatment time window, enhance the viability of neurons, reverse the penumbra, reduce the infarct volume, and promote the recovery of neurological function. Although various chemical and natural medicines are at different research stages, none of them has achieved a recognized definite curative effect. Therefore, active research and development of therapeutic drugs has important clinical significance.

Contents of the invention

The object of the present invention is to provide a new medicine for preventing and treating stroke, and the medicine is a coumarin derivative.

Another object of the present invention is to provide a method for preparing the coumarin derivative.

Another object of the present invention is to provide a pharmaceutical composition containing at least one coumarin derivative.

Another object of the present invention is to provide an application of such compounds in the preparation of medicaments for the prevention and treatment of stroke, especially ischemic stroke.

The present invention can adopt following technical scheme:

Specifically, the present invention relates to a coumarin derivative shown in formula I, or a pharmaceutically acceptable salt or prodrug thereof:

In formula I:

R ₁ and R ₂ are selected from hydrogen, hydroxyl, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, -NR ₁₁ R ₁₂ ; wherein, R ₁₁ and R ₁₂ can be the same or different, selected from hydrogen or C1-6 alkyl, or R ₁₁ and R ₁₂ can form a nitrogen-containing 5- or 6-membered heterocycloalkyl together with the nitrogen atom to which they are attached;

L represents -(CR _A R _B ) _n -, wherein R _A and R _B can be the same or different, each independently selected from hydrogen or C1-6 alkyl, n is 0, 1, 2, 3, 4 or 5;

A is selected from O or S;

R ₄ , R ₅ , and R ₆ are selected from hydrogen, hydroxyl, carboxyl, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, and cyano.

The method for preparing the compound of the present invention comprises the following steps:

Make the o-vanillin derivative shown in formula II and the acetoacetate shown in formula III cyclize under the existence of alkali to obtain the 3-acetyl coumarin derivative shown in formula IV, then in lithium chloride react with the Grignard reagent shown in formula V in the presence of , and then dehydrate with concentrated sulfuric acid to finally obtain the coumarin derivative shown in formula I.

Wherein, R ₁ -R ₂ , R ₄ -R ₆ , A, L are as defined above; R represents C1-6 alkyl; X represents halogen, preferably chlorine and bromine;

The base includes alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, triethylamine, piperidine, pyridine and the like.

In a preferred embodiment of the compounds of the invention, A represents O.

In a preferred embodiment of the compounds of the invention, A represents S.

In a preferred embodiment of the compound of the present invention, R ₁ and R ₂ represent C1-6 alkyl or C1-6 alkoxy, preferably methyl or methoxy; or R ₁ and/or R ₂ represent -NR ₁₁ R ₁₂

_In a preferred embodiment of the compounds of the invention, R4 represents halogen, preferably fluorine.

In a preferred embodiment of the compounds of the invention, R ₅ represents halogen or halogenated C1-6alkyl, preferably chlorine or trifluoromethyl.

In some preferred embodiments of the compounds of the present invention, said compounds are selected from:

definition

Unless defined otherwise, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned in this application are hereby incorporated by reference.

The term "C1-6 alkyl" is intended to mean a group obtained when one hydrogen atom is removed from a hydrocarbon. The alkyl group may be branched or straight chain and may contain 1-6, such as 1-5 carbon atoms, such as 1-4 carbon atoms, such as 1-3 carbon atoms, such as 1-2 carbon atoms . The term includes the subclasses n-alkyl (n-alkyl), sec-alkyl and tert-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Butyl, n-pentyl, n-hexyl.

The term "halogen" is intended to denote a substituent from main group 7 of the periodic table, such as fluorine, chlorine, bromine and iodine.

The term "nitrogen-containing 5- or 6-membered heterocycloalkyl" is intended to mean a heterocycloalkyl group comprising at least 1 nitrogen atom, 1-5 carbon atoms and optionally 0-3 other heteroatoms selected from oxygen, sulfur and nitrogen 5- or 6-membered monocyclic saturated ring groups, such as pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, oxazolidinyl, morpholinyl, thiomorph Linyl, etc.

The pharmaceutically acceptable salt of the coumarin derivative shown in formula I refers to the addition salt formed by the coumarin derivative shown in formula I and a pharmaceutically acceptable acid. The acid includes: inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid; or organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, succinic acid , tartaric acid, pamoic acid, glutamic acid, aspartic acid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid and malonic acid.

The term "prodrug" as used herein includes biohydrolyzable amides and biohydrolyzable esters, and also includes a) compounds according to the invention comprising biohydrolyzable functionality in such prodrugs, and b) compounds which can Compounds that are biologically oxidized or reduced at specified functional groups to yield pharmaceutical substances according to the invention.

The term "biohydrolyzable amide" as used herein is an amide of a drug substance (in the present invention, a coumarin derivative represented by formula I) which a) does not interfere with the biological activity of the parent substance, but confers on the substance in vivo Advantageous properties such as duration of action, onset of action, etc., or b) biologically inactive but readily converted by the subject in vivo to the biologically active ingredient. The advantage is, for example, that biohydrolyzable amides undergo oral absorption through the intestine and can be converted into coumarin derivatives of formula I in plasma.

The term "biohydrolyzable ester" as used herein is an ester of a drug substance (in the present invention, a coumarin derivative represented by formula I) which a) does not interfere with the biological activity of the parent substance, but confers on the substance in vivo Advantageous properties such as duration of action, onset of action, etc., or b) biologically inactive but readily converted by the subject in vivo to the biologically active ingredient. The advantage is, for example, that biohydrolyzable esters are orally absorbed through the intestine and can be converted into coumarin derivatives of formula I in plasma.

The term "pharmaceutically acceptable" as used herein means suitable for normal pharmaceutical use, ie not causing adverse events in patients and the like.

The present invention also relates to a pharmaceutical composition which uses the coumarin derivative represented by formula I or its pharmaceutically acceptable salt and prodrug as an active ingredient. The pharmaceutical composition may also contain pharmaceutically acceptable adjuvants or excipients.

The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal can be prepared by combining the coumarin derivative represented by formula I or its pharmaceutically acceptable salt, prodrug with pharmaceutically acceptable adjuvants or excipients. The content of the compound of the present invention in the pharmaceutical composition is usually 0.1-95% by weight.

Compounds of the invention in dosage unit form may be administered one or more times daily at appropriate intervals. Conveniently, dosage unit formulations contain from 0.1 mg to 1000 mg, preferably from 1 mg to 100 mg, such as 5-50 mg, of a compound of formula I. Suitable dosages of compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the condition being treated and other factors well known to the practitioner.

Such formulations include, for example, formulations suitable for oral (including sustained release or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ophthalmic, topical, dermal, Formulations for nasal, buccal or intradermal administration.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, gels , paste, etc.

As examples of pharmaceutically acceptable excipients and adjuvants that may be contained in pharmaceutical compositions, mention may be made of diluents, binders, lubricants, preservatives, thickeners, stabilizers, disintegrants, Wetting agents, emulsifiers, buffer substances, coloring agents, flavoring agents and fragrances, examples of which are water, physiological solutions of sodium chloride, vegetable oils, waxes, alcohols, triacetin, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates Compounds, talc, lanolin, petrolatum or their mixtures, etc.

The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

Another object of the present invention is to provide the application of coumarin derivatives shown in formula I or their pharmaceutically acceptable salts and prodrugs in the preparation of medicines, which are used for the prevention and treatment of stroke, especially ischemic stroke.

Beneficial effect

The present invention studies and analyzes the structural characteristics of the coumarin derivative shown in formula I of the present invention, and studies its pharmacodynamic characteristics in rats, confirming that it has the ability to prevent and treat stroke, especially ischemic stroke role. In addition, the coumarin derivatives shown in the formula I of the present invention show good therapeutic activity in the mouse cerebral ischemia-reperfusion test, which can significantly reduce the behavioral score of the cerebral ischemia-reperfusion mice, and can relieve Damage brain tissue and edema degree and water content, reduce the proportion of cerebral infarction, so it can be used to prevent and treat stroke, especially ischemic stroke.

detailed description

Hereinafter, the present invention is described in more detail to facilitate understanding of the present invention.

The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of synthesis. Compounds of formula I can be prepared, for example, using the reactions and techniques outlined below in conjunction with methods known in the art of synthetic organic chemistry or variations thereof as would be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in solvents appropriate to the reagents and materials employed and for the transformations to be effected. Furthermore, in the synthetic methods described below, it should be understood that all suggested reaction conditions (including choice of solvent, reaction atmosphere, reaction temperature, duration of experiments, and work-up procedures) were selected as standard conditions for this reaction, which should be referred to as organic Easily identified by those skilled in the art of synthesis. Not all compounds falling into a given class may be compatible with certain reaction conditions required in some of the described methods. These limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative approaches may be employed.

Example 1: (E)-3-(5-(benzofuran-7-yl)pent-2-en-2-yl)-6,7-dimethyl-2H-chromene-2-one ( Compound A)

Dissolve 1.50g of 2-hydroxy-4,5-dimethylbenzaldehyde in 200ml of absolute ethanol, add 20ml of ethyl acetoacetate and 2ml of piperidine, stir and heat, a solid appears after a few minutes, reflux for 25min, and cool to room temperature After filtration, 2.01 g of the desired product 3-acetyl-6,7-dimethyl-2H-chromen-2-one was obtained, with a yield of 93.1% and a content of 96.5%. ESI-MS: 217.08[M+H] ⁺

1.08 g of 3-acetyl-6,7-dimethyl-2H-chromen-2-one obtained in the above steps and 0.43 g of anhydrous lithium chloride were dissolved in 40 ml of dry tetrahydrofuran, and then newly prepared ( A solution of 2-(benzofuran-7-yl)ethyl)magnesium chloride 1.53g dissolved in 30ml of tetrahydrofuran, after reflux for 2h, the reaction mixture was cooled and 20ml of saturated ammonium chloride aqueous solution was added, and the aqueous phase was washed with diethyl ether (2× 75 ml), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. It was added to a 70°C hot solution containing 3ml of concentrated sulfuric acid and 20ml of glacial acetic acid, then stirred for 10min, the reaction mixture was poured into 100ml of ice water, then extracted with n-hexane (2×75ml), and the combined organic phase was washed with saturated sodium carbonate The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was separated by silica gel column chromatography (mobile phase: n-hexane:ethyl acetate=6:1) to obtain (E)-3-(5-(benzofuran-7-yl)pent-2-ene- 2-yl)-6,7-dimethyl-2H-chromen-2-one 1.02g, yield 57.1%, content 99.1%

ESI-MS: 359.16[M+H] ⁺

Elemental analysis: theoretical value/measured value, C(80.42/80.52), H(6.19/6.17), O(13.39/13.31)

¹ H NMR (400MHz, CDCl ₃ )δ7.73(d,1H),7.54(s,1H),7.49(d,1H),7.41(s,1H),7.13(q,1H),7.01(d, 1H),6.88(s,1H),6.54(d,1H),5.46(m,1H),2.56(t,2H),2.43(s,6H),2.28(m,2H),2.12(d,3H ).

Following a similar method, the following compounds were synthesized:

Example 2: (E)-3-(5-(4-fluoro-benzo[b]thiophen-7-yl)pent-2-en-2-yl)-6,7-dimethoxy-2H -Chromen-2-one (Compound B)

ESI-MS: 425.11[M+H] ⁺

Elemental analysis: theoretical value/measured value, C(67.91/67.78), H(4.99/5.07), F(4.48/4.57), O(15.08/15.01), S(7.55/7.57)

¹ H NMR (400MHz, CDCl ₃ )δ7.78(d,1H),7.74(d,1H),7.59(s,1H),7.31(d,1H),7.13(d,1H),6.87(s, 1H), 6.72(s, 1H), 5.42(m, 1H), 3.82(s, 6H), 2.56(t, 2H), 2.28(m, 2H), 2.12(d, 3H).

Example 3: (E)-3-(5-(2-chloro-benzo[b]thiophen-7-yl)pent-2-en-2-yl)-7-(pyrrolidin-1-yl) -2H-chromen-2-one (Compound C)

ESI-MS: 450.12[M+H] ⁺

Elemental analysis: theoretical value/measured value, C(69.40/69.52), H(5.38/5.47), Cl(7.88/7.79), N(3.11/3.08), O(7.11/7.14), S(7.13/7.00)

¹ H NMR (400MHz, CDCl ₃ ) δ7.62(d,1H),7.59(s,1H),7.47-7.32(m,3H),7.02(s,1H),6.67(d,1H),6.51( s,1H), 5.43(m,1H), 3.42(t,4H), 2.56(t,2H), 2.28(m,2H), 2.12(d,3H), 1.82(m,4H).

Example 4: (E)-7-(dimethylamino)-3-(5-(2-trifluoromethylbenzofuran-7-yl)hex-2-en-2-yl)-2H-color En-2-one (compound D)

ESI-MS: 456.17[M+H] ⁺

Elemental analysis: theoretical value/measured value, C(68.56/68.52), H(5.31/5.47), F(12.51/12.58), N(3.08/3.04), O(10.54/10.39)

¹ H NMR (400MHz, CDCl ₃ )δ7.72(d,1H),7.59(s,1H),7.47(d,1H),7.22(q,1H),7.02(d,1H),6.77(s, 1H),6.61(s,1H),6.52(s,1H),5.47(m,1H),3.02(s,6H),2.96(m,1H),2.34(m,2H),2.12(d,3H ), 1.24(s,3H).

Next, the pharmacological effects of representative compounds will be specifically explained through experimental examples.

Test Example 1: The effect of coumarin derivatives represented by formula I in treating ischemic stroke

The pharmacological experiment of making a focal cerebral ischemia model by mouse suture method is a commonly used animal experiment to verify that the drug has the effect of preventing and treating ischemic stroke. Prepare the ICR mouse cerebral ischemia-reperfusion model by the thread-embedding method (for details, see the Pharmacology, Pharmacology, and Toxicology section of "Guiding Principles for Preclinical Research of New Western Drugs", Pharmaceutical Administration of the Ministry of Health of the People's Republic of China, 1993: 73 ; "Pharmacological Experiment Methodology" second edition, People's Health Publishing House, 1982: 830, 1113), except the sham operation group, all the other groups were tested with this model mouse.

1. Animals

ICR mice, male, weighing 20-22 g. 20 rats in each group, divided into 8 groups, compound A low dose group: 1mg/kg; compound A medium dose group: 2mg/kg; compound A high dose group: 4mg/kg; compound B medium dose group: 2mg/kg; Compound C medium dose group: 2mg/kg; compound D medium dose group: 2mg/kg; sham operation group: give the same amount of normal saline as the drug experimental group for sham operation; model group: give the same amount of physiological saline as the drug experimental group Saline for cerebral ischemia-reperfusion surgery.

2. Experimental method

The mice were anesthetized by intraperitoneal injection of 10% chloral hydrate, the neck was cut midline, and the proximal end of the right common carotid artery, external carotid artery and its branches were separated and ligated. The right internal carotid artery was separated, the pterygognathic artery was separated downward along the internal carotid artery, and the root of the branch was ligated. Prepare the thread at the proximal end of the internal carotid artery, place an arterial clip at the distal end, make an incision at the bifurcation of the common carotid artery, insert a nylon thread, and tie the thread into the internal carotid artery, enter the cranium to the anterior cerebral artery, and block all blood flow sources of the middle cerebral artery . The arterial clamp was removed, the thread was tied tightly, leaving a 1cm long thread, and the skin was sutured. Administer intravenously 1 hour after ischemia. Continue ischemia for 1 hour before perfusion. Reperfusion was administered again for 8 hours. In the sham operation group, except for not inserting the wire, the rest of the steps are the same as above.

Observe the following indicators of the surviving mice after 24 hours of reperfusion:

(1) Observe the behavioral changes of the surviving mice after 24 hours, and conduct behavioral scoring: refer to Zea Longa’s 5-point scoring standard: 0 is normal without nerve damage symptoms; 1 is unable to fully extend the contralateral front paw; 2 points Turning in circles to the outside; 3 points, falling to the opposite side; 4 points, unable to walk spontaneously, loss of consciousness.

(2) Effects on the water content of brain tissue: Take 10 mice in each group and quickly decapitate to take the brain, weigh the wet weight of the left and right brain hemispheres respectively, dry them in an oven at 100°C, and weigh the dry weight after 24 hours, according to the following formula Calculate the water content of brain tissue: water content of brain tissue (%)=(wet weight-dry weight)/wet weight×100%.

(3) Effects on cerebral infarction volume: 10 mice were taken from each group, and the brains were sacrificed. Coronal brain slices with a thickness of about 2 mm were cut out, placed in 2% TTC solution immediately, and incubated at 37° C. for 30 minutes. The infarcted area appears white, and the non-infarcted area appears red. A digital camera was used to shoot and record, and the area of each area was measured by computer image processing, and the percentage (%) of the infarct area in the whole brain tissue was calculated.

3. Experimental results

(1) Effects of test compounds on behavioral scores of cerebral ischemia-reperfusion mice

Table 1: Behavioral scores of mice in each experimental group after cerebral ischemia-reperfusion

group Dose (mg/kg) Behavioral score (points) mock surgical group - 0 model group - 3.7±0.5 Compound A low dose group 1 2.6±0.4 ^# Compound A middle dose group 2 2.1±0.6 ^# Compound A high dose group 4 1.7±0.4 ^# Compound B middle dose group 2 2.3±0.5 ^# Compound C middle dose group 2 2.1±0.4 ^# Compound D middle dose group 2 1.9±0.6 ^#

Note: Compared with the model group, ^# P<0.05

The test results showed that the mice in the sham operation group did not show any abnormal symptoms. However, the mice in the model group showed symptoms of nerve injury, such as turning to the outside, or falling to the opposite side, or unable to fully extend the contralateral forepaw. The low, medium and high dose groups of compound A can significantly reduce the behavioral scores of ischemia-reperfusion mice, and the reduction degree of the behavioral scores has a significant dose-dependent relationship with compound A, and compounds B, C and D can also significantly reduce The behavioral scores of ischemia-reperfusion mice were reduced, which proved that the above-mentioned test compound could obviously improve the symptoms of nerve injury caused by ischemia-reperfusion.

(2) Effect of test compound on water content in brain tissue of cerebral ischemia-reperfusion mice

Table 2: Effects on water content in brain tissue of ischemia-reperfusion mice

Note: Compared with the model group, ^# P<0.05

The test results showed that there was no edema in the left and right brain tissues of the mice in the sham operation group. The water content of the brain tissue on the ischemic side of the model group was significantly higher than that of the sham operation group, and also higher than that of the left brain tissue. However, the water content of brain tissue in the ischemic side of the mice in the low, medium and high dose groups of compound A was significantly lower than that of the model group, and showed a certain dose-dependent relationship. Compounds B, C and D could also significantly reduce Brain tissue water content, the results prove that the above test compound can reduce the edema degree of ischemia-reperfusion injury brain tissue, and reduce its water content.

(3) Effect of test compound on cerebral infarct size in mouse cerebral ischemia-reperfusion model

Table 3: Cerebral infarction area after cerebral ischemia-reperfusion in mice in each experimental group

Note: Compared with the model group, ^# P<0.01

The test results showed that there was no infarction in the brain tissue of mice in the sham operation group. The brain tissue of the ischemic side of the mice in the model group had obvious infarction, and the cerebral infarction/whole brain (%) was 49.3±2.9%. The low, medium and high dose groups of compound A can significantly reduce the percentage of cerebral infarction, and the degree of reduction has a dose-dependent relationship with the drug. Compounds B, C and D can also significantly reduce the percentage of cerebral infarction. Cerebral infarction caused by cerebral ischemia-reperfusion injury in mice has a very good protective effect.

The preferred embodiments of the present invention have been described above, but they are not intended to limit the present invention. Modifications and changes to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (10)

1. the coumarin derivative shown in a kind of Formulas I, or its pharmaceutically acceptable salt, prodrug：

In Formulas I：

R₁、R₂Selected from hydrogen, hydroxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy carbonyls ,- NR₁₁R₁₂；Wherein, R₁₁、R₁₂Can be with identical or different, selected from hydrogen or C1-6 alkyl, or R₁₁、R₁₂The nitrogen that can be connected with it Atom forms 5 or 6 nitrogenous circle heterocycles alkyl together；

L represents-(CR_AR_B)_n-, wherein R_A、R_BHydrogen or C1-6 alkyl can be each independently selected from identical or different, n is 0,1, 2nd, 3,4 or 5；

A is selected from O or S；

R₄、R₅、R₆Selected from hydrogen, hydroxyl, carboxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxies Carbonyl, cyano group.

2. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special Levy and be, the A represents O.

3. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special Levy and be, the A represents S.

4. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special Levy and be, the R₁And R₂Represent C1-6 alkyl or C1-6 alkoxies, preferably methyl or methoxy；Or R₁And/or R₂Represent- NR₁₁R₁₂。

5. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special Levy and be, the R₄Represent halogen, preferably fluorine.

6. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special Levy and be, the R₅Represent halogen or halo C1-6 alkyl, preferably chlorine or trifluoromethyl.

7. the coumarin derivative shown in Formulas I according to claim 1, or its pharmaceutically acceptable salt, prodrug, it is selected From：

8. a kind of pharmaceutical composition, it includes the cumarin shown at least one Formulas I according to claim any one of 1-7 Derivative or its pharmaceutically acceptable salt, prodrug, and pharmaceutically acceptable assistant agent or excipient.

9. it is coumarin derivative shown in Formulas I or its pharmaceutically acceptable salt according to claim any one of 1-7, preceding Application of the medicine in treatment cerebral apoplexy particularly cerebral arterial thrombosis.

10. a kind of method of the coumarin derivative shown in Formulas I prepared according to claim 1, it includes following mistake Journey：

Making o-vanillin derivative shown in Formula II, cyclization obtains formula IV in the presence of base with the acetoacetic ester shown in formula III Shown 3- acetyl group coumarin derivatives, then react, then pass through in the presence of lithium chloride with the RMgBr shown in Formula V again The concentrated sulfuric acid is dehydrated, and finally gives the coumarin derivative shown in Formulas I：

Wherein, R₁-R₂、R₄-R₆, A, L definition as described in the appended claim 1；R represents C1-6 alkyl；X represents halogen, preferably chlorine And bromine；

Alkali includes alkoxide such as sodium methoxide, caustic alcohol, potassium ethoxide, triethylamine, piperidines, pyridine etc..