CN110862349A - Edaravone analogue and preparation method and application thereof - Google Patents

Abstract

The edaravone analogue and the preparation method and the application thereof, the compound conforms to the following structural general formula:

wherein R is₁And R₂Is methyl, methoxy, ethyl, isopropyl, tert-butyl or sec-butyl. The compound of the present invention has GABAA receptor enhancing activity and free radical scavenging activity, and has neuroprotective effect, and the compound of the present invention can be used as a preventive and therapeutic agent for stroke.

Description

Edaravone analogue and preparation method and application thereof

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to an edaravone analogue, and a preparation method and application thereof.

Background

Stroke has the characteristics of high morbidity, high mortality, high disability rate and the like, and is one of the main diseases seriously harming human life. The pathogenesis of the stroke is complex, and the energy metabolism disorder, the toxicity of excitatory amino acid, the inflammatory reaction, the apoptosis and the like participate in the pathophysiological change process. Studies have shown that a large number of oxygen radicals are produced during cerebral ischemia and reperfusion. Oxidative damage caused by a large number of free radicals is one of the key factors in neuronal cell damage.

The edaravone (3-methyl-1-phenyl-2-pyrazoline-5-ketone) is a low molecular weight antioxidant drug, can eliminate various free radicals, inhibit lipid peroxidation, resist neuronal oxidative damage, and reduce cerebral ischemia and cerebral edema. Edaravone was approved by japan in 2001 as a drug for the treatment of acute cerebral infarction, is the only FDA-approved free radical scavenger to market, and was approved by the FDA as an orphan drug of ALS in 5 months in 2017.

Glutamate (Glu) is the most major excitatory neurotransmitter in the central nervous system, and is released in large amounts when ischemia occurs, acting on AMPA receptors resulting in edema, acting on NMDA receptors resulting in large influx of calcium ions and subsequent generation of large amounts of free radicals.

Propofol (2, 6-diisopropylphenol) is an intravenous short-acting anesthetic and is widely used for anesthesia and sedation. In addition to its use as an anesthetic, propofol can also exert non-anesthetic effects such as antiemetic, immunomodulating, anxiolytic and analgesic effects (CNSNeuroci ther.2008,14(2): 95-106). More importantly, propofol has been shown to have neuroprotective effects in a number of in vivo models, such as cerebral ischemia or ischemia reperfusion, Parkinson's disease, intracerebral hemorrhage, cerebral resuscitation, and spinal cord ischemia (Int JNeurosci.2019129 (2): 155-164). Also, in vitro studies have demonstrated neuroprotective effects of propofol in different models (Oxid Med Cell Longev.2018: 1725191). Propofol is an enhancer and agonist of gamma-aminobutyric acid (GABA) receptor a (GABAA receptor). Gamma-aminobutyric acid is the major inhibitory neurotransmitter in the CNS. Cell membrane depolarization is the initial stage of nerve injury, propylpoisePhenols can hyperpolarize cell membranes by GABA potentiation and GABAA agonistic activity, antagonize depolarization. Secondly, the sedative effect of propofol reduces respiratory rate, reduces total energy consumption of the human body, and the reduction of glucose consumption can alleviate ketoacidosis and improve local cerebral blood flow. The chemical structure of propofol is similar to that of antioxidant vitamin E, and clinical research shows that propofol can increase the antioxidant capacity of blood plasma. In vitro and in vivo studies have shown that propofol can directly scavenge ROS and inhibit free radical production and lipid peroxidation to protect neurons against oxidative stress. Studies have also shown that propofol can inhibit presynaptic voltage-dependent Na⁺A channel, which prevents the synaptosome from releasing Glu. In addition, propofol can inhibit phosphorylation of NMDAR, reduce Glu and NMDAR reactivity in cortex and hippocampal neurons, and significantly reduce NMDA-mediated Ca²⁺And (4) internal flow. Moreover, propofol accelerates Glu metabolism by increasing excitatory amino acid transporter (EAAT 3) activity.

When stroke occurs, a large number of pathophysiological processes are activated, so that it is difficult to obtain clinically satisfactory treatment effect on only one target (China New medicine J, 2019,28(6): 683-charge 688). Therefore, a multi-target, multi-mechanism stroke therapeutic drug is an important point for future research. According to the invention, a proper group is introduced on the benzene ring of the edaravone, so that the edaravone has the structural characteristic of propofol with GABAA receptor activity, and the discovery of a novel nerve protection drug with multiple targets and multiple pharmacological action mechanisms is realized.

Disclosure of Invention

The technical problem to be solved is as follows: the invention provides an edaravone analogue, a preparation method and application thereof, wherein the edaravone analogue has antioxidant activity and GABAA receptor enhancing effect, and the compound with multiple pharmacological action mechanisms has better in-vivo neuroprotective effect than edaravone.

The technical scheme is as follows: the edaravone analogue conforms to the following structural general formula:

wherein R is₁And R₂Is methyl, methoxy, ethyl, isopropyl, tert-butyl or sec-butyl.

The edaravone analogue has a structural formula which is preferably any one of the following compounds:

the edaravone analogue can be applied to preparation of medicines for preventing or treating cerebral apoplexy.

The synthesis of the compounds of the present invention can be represented by the following synthetic scheme.

Has the advantages that: hydroxyl and proper alkyl groups are introduced into the benzene ring of the edaravone, so that the edaravone has the GABAA receptor enhancing activity while the antioxidation is enhanced. The enhanced antioxidant activity and GABAA receptor activity contribute to neuroprotection in the event of stroke. As a result, the compound of the present invention has approximately twice the neuroprotective activity of edaravone in animal models.

Drawings

FIG. 1: DPPH free radical is clearly active. Edaravone (edaravone), 5, 10 scavenges DPPH free radical activity at different concentrations. The results show the EC of edaravone₅₀EC of 0.326mM,5₅₀Is an EC of 0.159mM,10₅₀Is 0.183mM.

FIG. 2: TTC staining of brain sections after rat MACO model. The brain slices of the sham-operated group are bright red and have no damaged brain tissues; the whitening area, namely the infarct area, is arranged on the right side of the brain slice of the operation group; the infarct size of the edaravone (edaravone) treated group was significantly reduced, and the right edges of the 2 nd and 3 rd sections were slightly white; when compounds 5 and 10 of the present invention were administered in equimolar amounts to edaravone, the infarct size of rat brain sections was small.

FIG. 3: infarct size histogram. Figure 3 is a bar graph representation of the infarct size scan of figure 2. The figure shows that the infarct size of the operative group is 36%, the infarct size of the edaravone-treated group is reduced to only 13.5%, the infarct size of 5 is only 7.3%, and the infarct size of 10 is 10%. The results show that the compounds of the invention are more therapeutically effective than edaravone.

FIG. 4: GABA-potentiating activity and direct agonism of compound 10.

Note: a: enhanced activity of 5 μ M10 on 12 μ M GABA; b: enhanced activity of 20 μ M10 on 12 μ M GABA; c: enhanced activity of 40 μ M10 on 12 μ M GABA; d: 500 μ M10 direct agonist activity of the GABAA receptor. From the graph, it is understood that 10 doses enhance the GABA electric signal (A to C). No enhancement effect is generated at 5 mu M, the electric signal is obviously enhanced at 20 mu M, and the enhancement effect is very obvious at 40 mu M; d: compound 10500 μ M had a significant direct GABAA receptor activating effect in the absence of GABA. This experiment shows that the compounds of the present invention have an enhanced GABA activity and direct GABAA receptor activation at high concentrations.

Detailed Description

The following examples are given to enable a person skilled in the art to fully understand the invention, but do not limit it in any way.

Example 14-Nitro-2, 6-diisopropylphenol (1)

In the flask were added 100mL of tetrahydrofuran and 3.56g (20mmol) of propofol, and the mixture was stirred for 10 minutes. 4.8mL (40mmol) of tert-butyl nitrite is added dropwise to the solution under ice bath conditions, and the reaction is carried out overnight at 40 ℃. And after the reaction is stopped, spin-drying the solution to obtain a tan solid, adding 150mL of petroleum ether, grinding to a fine solid, performing ultrasonic treatment for 5min, and filtering to obtain an orange crude product. The crude product was further subjected to silica gel column chromatography (PE: EA: 20:1, R)_f0.3) to give a pale yellowish white top-quality product with a yield of 1.2g of 27%.¹HNMR(400MHz,CDCl₃)δ:7.98(s,2H,arom),5.51(s,1H,OH),3.16(m,2H,C-H(CH₃)₂),1.30(d,J＝6.8Hz,12H,CH₃).

Example 24-Nitro-2, 6-diisopropylacetylphenol (2)

4-nitro-2, 6-diisopropyl phenol (1)2 is added into a 125mL pressure-resistant bottle in sequenceg (9mmol), 10mL of acetic anhydride, replaced with argon, and reacted at 160 ℃ overnight. After the reaction was terminated, 100mL of ethyl acetate was added, and the organic layer was washed with 300mL of water 5 times, saturated brine 2 times, and dried over anhydrous sodium sulfate. Filtration and spin-drying gave 2.3g of 4-nitro-2, 6-diisopropylacetylphenol (2), 96% yield.¹H NMR(400MHz,CDCl₃)δ:7.98(s,2H,arom),2.95(m,2H,CH(CH₃)₂),2.39(s,3H,CH₃),1.24(d,J＝6.8Hz,12H,CH₃).

Example 34-amino-2, 6-diisopropylacetylphenol (3)

2.3g of 4-nitro-2, 6-diisopropylacetylphenol (2) was dissolved in 25mL of tetrahydrofuran and 25mL of methanol, 0.25g of 10% palladium on carbon was added, and the mixture was reacted with hydrogen overnight. After the reaction is stopped, the palladium-carbon is filtered and removed, the filtrate is dried by spinning, and silica gel column chromatography is carried out (PE: EA is 5:1, R)_f0.4) gave 2g of 4-amino-2, 6-diisopropylacetylphenol (3) as a pale yellow white solid in 98% yield.¹H NMR(400MHz,DMSO-d₆)δ:6.3(s,2H,arom),4.85(s,2H,NH₂),2.68(m,2H,CH(CH₃)₂),2.22(s,2H,CH₃),1.03(d,J＝6.8Hz,12H,CH₃).MS(ESI,m/z):258.2[M+Na]+

Example Synthesis of 43 ', 5 ' -diisopropyl-4 ' -acetoxyedaravone (4)

2g (8.5mmol) of 4-amino-2, 6-diisopropylacetylphenol (3) is dissolved in 6mL of acetic acid (102mmol) and 17mL of concentrated hydrochloric acid (204mmol), and an aqueous solution (3.7mL, 204mmol) of sodium nitrite (0.88g,12.7mmol) is added dropwise under ice bath conditions, maintaining the temperature at 0-5 ℃. After 1 hour of reaction, a concentrated hydrochloric acid solution (4.25mL, 51mmol) of stannous dichloride dihydrate (5.75g, 25.5mmol) was added dropwise to the above diazonium salt in an argon atmosphere, and the temperature was maintained at 0 to 5 ℃. After reacting for 6h, adjusting the pH value to 9 by 2N sodium hydroxide, precipitating a large amount of stannous hydroxide precipitate, filtering by using kieselguhr, extracting the filtrate by using ethyl acetate for 3 times, washing the kieselguhr by using ethyl acetate for 3 times, combining the obtained organic layers, washing by using saturated saline solution for 2 times, fully drying by using anhydrous sodium sulfate, filtering and spin-drying to obtain an orange oily liquid. Dissolving the oily liquid obtained in the previous step with 15mL of acetic acid, stirring for 10min under the condition of cold water bath, dropwise adding 1.2mL (9.35mmol) of ethyl acetoacetate, and maintaining the temperature at 0-5 ℃. After reacting for 15min, the mixture was added to a silica gel column without further treatment (PE: EA: 2:1, R)_f0.3) to obtain 1g of 3 ', 5 ' -diisopropyl-4 ' -acetoxy edaravone (4) as a yellow solid, and the total yield of the two steps is 39%.¹H NMR(400MHz,CDCl₃)δ:7.66(s,2H,arom),3.39(s，2H,CH₂)，2.9(m,2H,CH(CH₃)₂),2.34(s,3H,CH₃),2.18(s,3H,CH₃),1.21(d,J＝6.8Hz,12H,CH₃).MS(ESI,m/z):317.2[M+H]⁺.

Example Synthesis of 53 ', 5 ' -diisopropyl-4 ' -hydroxyedaravone (5)

0.4g (1.26mmol) of 3 ', 5 ' -diisopropyl-4 ' -acetoxyedaravone (4), 2.5mL of 2N sodium hydroxide, 7.5mL of ethanol were sequentially added to a pressure-resistant bottle, and the mixture was replaced with argon and reacted at 70 ℃ overnight. After the reaction was terminated, pH was adjusted to 3 with 3N hydrochloric acid, extraction was performed 3 times with ethyl acetate, washed 2 times with saturated brine, sufficiently dried over anhydrous sodium sulfate, and spin-dried to obtain 0.3g of 3 ', 5 ' -diisopropyl-4 ' -hydroxyedaravone (5) as a yellow solid, with a yield of 86.7%.¹H NMR(400MHz,CDCl₃)δ:7.46(s,2H,arom),4.81(s,1H,OH),3.4(s,2H,CH₂),3.16(m,2H,CH(CH₃)₂),2.19(s,3H,CH₃),1.29(d,J＝6.8Hz,12H,CH₃).MS(ESI,m/z):297.2[M+Na]⁺The structural formula is:

EXAMPLE 62 Synthesis of tert-butyl-4-nitro-6-methylphenol (6)

The synthesis method is the same as that of compound 1. 3.28g (20mmol) of 2-tert-butyl-6-methylphenol, 4.8mL (40mmol) of tert-butyl nitrite, and 100mL of tetrahydrofuran. After the reaction treatment, 1.5g, R of light yellow white solid 2-tert-butyl-4-nitro-6-methylphenol (6) is obtained_f0.2(PE: EA ═ 20:1), yield 36%.¹H NMR(400MHz,CDCl₃)δ:8.09(d,J＝2.8Hz,1H,arom),7.95(d,J＝2.8Hz,1H,arom),5.45(s,1H,OH),2.32(s,3H,CH₃),1.43(s,9H,CH₃).MS(ESI,m/z):210.1[M+H]⁺.

Example 72 Synthesis of tert-butyl-4-nitro-6-methylacetophenol (7)

The synthesis method is the same as that of the compound 2. 1.5g (7.2mmol) of 2-tert-butyl-4-nitro-6-methylphenol, and 1.75g, R, of 2-tert-butyl-4-nitro-6-methylacetophenol (7) as a pale yellow solid was obtained after the reaction_f0.8(PE: EA ═ 20:1), yield 97%.¹H NMR(400MHz,CDCl₃)δ:8.16(d,J＝2.8Hz 1H,arom),8.01(d,J＝2.8Hz,1H,arom),2.4(s,3H,CH₃),2.22(s,3H,CH₃),1.39(s,9H,CH₃).

Example Synthesis of 82-tert-butyl-4-amino-6-methylacetophenol (8)

The synthesis method is the same as that of compound 3. 1.75g (7mmol) of 2-tert-butyl-4-nitro-6-methylacetophenol (7), 0.2g of 10% palladium on carbon, 25mL of tetrahydrofuran and 25mL of methanol. After the reaction treatment, 1.5g, R of 2-tert-butyl-4-amino-6-methylacetophenol (8) was obtained as a pale yellow solid_f0.5(PE: EA ═ 5:1), yield 97%.¹H NMR(400MHz,DMSO-d₆)δ:6.43(d,J＝2.8Hz,2H,arom),6.28(d,J＝2.8Hz,2H,arom),4.86(s,2H,NH₂),2.26(s,3H,CH₃),1.99(s,9H,CH₃),1.87(s,3H,CH₃).MS(ESI,m/z):221.1[M+H]⁺.

Example Synthesis of 93 ' -tert-butyl-5 ' -methyl-4 ' -acetoxy-edaravone (9)

The synthesis method is the same as that of compound 4. 0.5g (2.25mmol) of 2-tert-butyl-4-amino-6-methylacetophenol (8), 6mL of concentrated hydrochloric acid, 5mL of acetic acid, 0.24g (3.5mmol) of sodium nitrite, 0.6mL of water, 1.5g (6.75mmol) of stannous chloride dihydrate and 0.35mL (2.5mmol) of ethyl acetoacetate. After the reaction treatment, 0.24g, R of 3 ' -tert-butyl-5 ' -methyl-4 ' -acetoxy-edaravone (9) was obtained as a pale yellowish white solid_f0.3(PE: EA ═ 3:2), yield 5%.¹H NMR(400MHz,CDCl₃)δ:7.76(d,J＝2.8Hz,2H,arom),7.62(d,J＝2.8Hz,2H,arom),3.41(s,2H,CH₂),2.34(s,3H,CH₃),2.19(s,3H,CH₃),2.14(s,3H,CH₃),1.35(s,9H,CH₃).MS(ESI,m/z):325.2[M+Na]⁺.

Example 103 Synthesis of ' -tert-butyl-5 ' -methyl-4 ' -hydroxyedaravone (10)

The synthesis method is the same as that of compound 5. 3 ' -tert-butyl-5 ' -methyl-4 ' -acetoxyedaravone (9)0.24g (0.8mmol), 2N sodium hydroxide 1.6mL, ethanol 4.8 mL. After the reaction treatment, 0.1g, R of 3 ' -tert-butyl-5 ' -methyl-4 ' -hydroxyedaravone (10) was obtained as a pale yellowish white solid_f0.25(PE: EA ═ 3:2), yield 50%.¹H NMR(400MHz,CDCl₃)δ:7.52(d,J＝2.8Hz,2H,arom),7.41(d,J＝2.8Hz,2H,arom),4.74(s,1H,OH),3.4(s,2H,CH₂),2.27(s,3H,CH₃),2.19(s,3H,CH₃),1.42(s,9H,CH₃).MS(ESI,m/z):261.2[M-H]^-The structural formula is:

EXAMPLE 11 DPPE radical scavenging Activity assay

1, 1-Diphenyl-2-trinitrophenylhydrazine (DPPH) is a stable free radical with an absorption maximum at 517 nm. When DPPH is cleared, the absorbance A is reduced, and the stable free radical DPPH provides a simple and reliable model for in vitro free radical scavenging activity detection.

The experimental steps are as follows:

① solution was prepared with DPPH concentration of 1.2mM, and the sample solution was prepared with various concentration gradients of 0, 0.1, 0.15, 0.2, 0.3, 0.6, 1.2mM

② measurement, adding 500. mu.L of DPPH solution and 500. mu.L of sample solution at each concentration into a 96-well plate, incubating at room temperature in the dark for 30min, and measuring the absorbance at 517nm of each well by using a microplate reader.

③ calculation of the absorbance A of a 0mM sample solution₀And the absorbance of the rest concentration is A according to a clearance formula: inhibition% ((a))₀-A)/A₀Clearance was calculated for each concentration of sample at 100%.

④ data processing, using Origin 8.5.1 to make clearance curve of sample, fitting equation Logistic equation to obtain EC of sample₅₀Value of

⑤ Experimental results, EC₅₀: edaravone: 0.326 mM; compound 5: 0.158 mM;compound 10: 0.183mM.

Example 12 Experimental methods for rat MACO model

1. Animals Sprague-Dawley rats (9-10 weeks old, 250-270 g). Food and water were taken ad libitum with maintaining room temperature 22 + -2 deg.C and light (12 hours light and shade cycle). Animals were randomly assigned to experimental groups by computer. The experimenter marks all animals according to the randomization schedule before assignment. The experiments were performed by researchers who did not know to which group the animals belong.

2. Transient cerebral ischemia model experimental protocol reference was made to the transient cerebral ischemia model described by Zhou L et al [ nat med,2010,16,1439-43 ]. Briefly, SD rats were anesthetized with chloral hydrate (350mg/kg, ip) and 4/0 surgical nylon monofilament circular tips were introduced into the left internal carotid artery through the external carotid stump, advancing 20-21mm at the carotid bifurcation until slight resistance was felt. At this point, the intraluminal filaments occlude all blood sources of the middle, internal, anterior and posterior cerebral arteries. Throughout the process, the animal body temperature was maintained at 37. + -. 0.5 ℃. The tether was left in place for 120 minutes and then removed for reperfusion. Immediately after removal of the plug wire, administration was via the tail vein. In sham animals, the occlusive filament was inserted only 7mm above the carotid bifurcation.

3. Evaluation results infarct volume measurements were performed 2 hours after MCAO. Brains were removed quickly and frozen at-20 ℃ for 5 min. Coronal sections of 1-2 mm were prepared, immersed in 2% TTC and stained at 37 ℃ for 4 h. Infarct volume is expressed as the percentage area of coronal sections in infarcted hemispheres: I/R: 36 percent; edaravone: 13.5 percent; compound 5: 7.3 percent; compound 10: 10 percent.

Example 13 GABA potentiating and direct agonistic assays

1 preparation of reagents

1.1 sucrose-rich slice: 85mmol/L NaCl,2.5mmol/L KCl,1.25mmol/L NaH₂PO₄，25mmol/L NaHCO₃25mmol/L glucose, 75mmol/L sucrose, 0.5mmol/L CaCl₂，4mmol/L MgCl₂。

1.2 artificial cerebrospinal fluid: 119mmol/L NaCl,2.5mmol/L KCl,1.25mmol/L NaH₂PO₄,2.5mmol/L CaCl₂，1.3mmol/L MgCl₂,1.3mmol/L NaHCO₃10mmol/L glucose.

1.3 electrode internal solution to record inhibitory postsynaptic current: 135mmol/L CsCl,2mmol/L Na₂ATP,0.2mmol/L EGTA,10mmol/L HEPES,0.3mmol/L Na₃GTP,10mmol/L glucose, osmolality 310mOsm, adjusted to pH 7.2 with CsOH.

2 recording of GABA induced currents

And (3) observing for at least 5min before recording by adopting a patch clamp voltage clamp whole cell recording mode, and ensuring that the cells are in a stable state. Adding Na into perfusion liquid⁺Channel blockers (TTX, 1. mu.M), AMPA receptor blockers (CNQX), 10. mu.M NMDA receptor blockers (APV, 50. mu.M), spontaneous inhibitory postsynaptic currents were recorded at-70 mV in the clamped cells, GABA or drugs were perfused separately according to experimental design, and their induced inhibitory responses were observed. The serial impedance was continuously observed during the recording process to prevent resealing after cell rupture, and discarded if the difference from the background value was greater than 20%.

3 results of the experiment

The experiment shows that 12 mu M GABA generates obvious Cl^-Current, 5 μ M Compound 10 did not have potentiating effect on GABA (A); compound 10 at 20 μ M had a significant GABA potentiating effect (B); compound 10 at 40 μ M had significant GABA potentiating effects (C); showing better dose dependence. As can be seen from Panel D, 500 μ M of Compound 10 directly activated the GABAA receptor. It is thus understood that compound 10 has both GABA potentiating effect and GABAA agonistic activity.

Claims (5)

1. The edaravone analogue is characterized by conforming to the following structural formula:

wherein R is₁And R₂Is methyl, methoxy, ethyl, isopropyl, tert-butyl or sec-butyl.

2. The edaravone analog according to claim 1, characterized by the structural formula of any one of the following compounds:

3. the edaravone analog according to claim 1 or 2, characterized by the preparation process: nitrifying the 2, 6-disubstituted phenol by using t-BuONO at room temperature, wherein the molar ratio of the 2, 6-disubstituted phenol to the t-BuONO is 1:2, so as to obtain 4-nitro-2, 6-disubstituted phenol; acetylation is carried out on phenolic hydroxyl of the 4-nitro-2, 6-disubstituted acetyl phenol by acetic anhydride at 160 ℃, wherein the molar ratio of the phenolic hydroxyl to the acetic anhydride is 1: 10; the obtained product is used for 1atm of H₂Reducing under the catalysis of Pd/C catalyst to obtain 4-amino-2, 6-disubstituted acetyl phenol; NaNO for amino group of 4-amino-2, 6-disubstituted acetylphenol₂Diazotizing at 0-5 ℃, wherein the amino group of the 4-amino-2, 6-disubstituted acetyl phenol and NaNO₂In a molar ratio of 1:1.4, followed by SnCl at the same temperature₂Reducing the amino group of the 4-amino-2, 6-disubstituted acetyl phenol with SnCl₂The molar ratio of the obtained product to the obtained product is 1:3, and a corresponding phenylhydrazine compound is obtained; the obtained phenylhydrazine compound reacts with ethyl acetoacetate at 0-5 ℃ by using acetic acid as a solvent to obtain 3 ', 5 ' -disubstituted-4 ' -acetoxy edaravone, the molar ratio of the phenylhydrazine compound to the ethyl acetoacetate is 1:1.1, acetyl of the phenylhydrazine compound is hydrolyzed and removed by NaOH at room temperature to obtain 3 ', 5 ' -disubstituted-4 ' -hydroxy edaravone, and the molar ratio of the acetyl of the 3 ', 5 ' -disubstituted-4 ' -acetoxy edaravone to the NaOH is 1: 4.

4. Use of the edaravone analogue of claim 1 or 2 in the preparation of a medicament for the prevention or treatment of stroke.

5. A pharmaceutical composition for preventing or treating stroke, characterized in that the active ingredient is the compound according to claim 1 or 2.

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