CN115974854B

CN115974854B - Phenol alkenyl phthalide pyrazolone compound, and preparation method and application thereof

Info

Publication number: CN115974854B
Application number: CN202310109772.8A
Authority: CN
Inventors: 邓勇; 丛士钦; 施怡春; 余光俊; 张杨惠; 莫金兰
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2023-02-14
Filing date: 2023-02-14
Publication date: 2024-04-19
Anticipated expiration: 2043-02-14
Also published as: CN115974854A

Abstract

The invention discloses a phenol alkenyl phthalazinone pyrazolone compound (I), a preparation method and a pharmaceutical composition thereof and application thereof in preparing medicines for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer's disease, frontotemporal dementia, prion disease, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic cerebral apoplexy, hemorrhagic cerebral apoplexy, nerve injury caused by brain trauma and other diseases;

Description

Phenol alkenyl phthalide pyrazolone compound, and preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a phenol alkenyl phthalide pyrazolone compound (I), a preparation method and a pharmaceutical composition thereof, and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic cerebral apoplexy, hemorrhagic cerebral apoplexy, nerve injury caused by brain trauma and the like.

Background

Neurodegenerative diseases are the general names of diseases caused by chronic progressive degenerative changes of central nervous tissue, and include Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's disease (Huntington disease, HD), amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS), multiple sclerosis (Multiple sclerosis, MS) and the like, and the pathogenesis thereof is closely related to oxidative stress, neuroinflammation and corresponding injury. Oxidative stress is mediated by reactive oxygen (Reactive oxygen species, ROS) radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, among others. Under normal physiological conditions, ROS production levels are in a state of dynamic equilibrium with the organism's antioxidant capacity, and oxidative stress (Oxidative stress) occurs when ROS production exceeds the cell's antioxidant capacity, whereas the brain is particularly sensitive to oxidative stress, thereby inducing a variety of neurological diseases. In addition, it has been found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve injury caused by brain trauma are also closely related to oxidative stress and nerve inflammation of the body.

Vascular dementia (Vascular Dementia, VD) is a clinical syndrome of intellectual and cognitive dysfunction caused by various types of cerebrovascular diseases including ischemic cerebrovascular diseases, hemorrhagic cerebrovascular diseases, acute and chronic hypoxic cerebrovascular diseases, etc. Due to the complex pathogenesis of vascular dementia, no medicine capable of blocking the development of the disease exists at present, and clinical treatment is mainly performed to improve the blood circulation and the brain metabolism of the brain and strengthen the nutrition of the brain.

Alzheimer's Disease (AD) is a central nervous system degenerative disease mainly composed of progressive cognitive disorder and memory impairment, and the incidence of which is in an increasing trend year by year, becoming a high-incidence disease next to cardiovascular disease and cancer. With the acceleration of the aging process of the global population, the incidence rate of the disease is obviously increased. It is estimated that over 5000 tens of thousands of people worldwide are currently suffering from dementia, and the total cost of treatment and care is over dollars 1 trillion in 2018, and the number of people suffering from dementia will increase to 1.52 billion by 2050. AD is clinically manifested by reduced memory, orientation, thinking and judgment, reduced daily life, even abnormal mental behavior symptoms, and the like, which makes patient care difficult and places a heavy burden on society and families. Currently approved drugs for the treatment of mild/moderate AD are acetylcholinesterase (AChE) inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists for the treatment of severe AD. Clinical application shows that the medicines can relieve AD symptoms by improving the level of acetylcholine in patients or inhibiting the excitotoxicity of excitatory amino acids, but can not effectively prevent or reverse the course of the disease, and can also cause serious toxic and side effects such as illusion, consciousness chaos, dizziness, nausea, hepatotoxicity and the like, so that the long-term curative effect is not ideal. Thus, there is a great clinical need to develop new therapeutic agents for AD that have both symptomatic improvement and altered course of disease.

The pathogenesis of AD is complex due to various factors, and the pathogenesis of AD is not completely elucidated yet. However, studies have shown that a variety of factors such as decreased levels of acetylcholine in the brain, excessive production and deposition of beta-amyloid, platelet aggregation in brain blood vessels, disturbed metal ion metabolism, disturbed Ca ²⁺ balance, neurofibrillary tangles caused by tau-protein hyperphosphorylation, excessive glutamate receptor activity, oxidative stress to produce large amounts of Reactive Oxygen Species (ROS) and free radicals, and neuroinflammatory reactions play an important role in the pathogenesis of AD. For the above-mentioned pathogenesis, researchers have adopted the traditional "one drug one target" drug design strategy, and found a large number of drugs with high activity and high selectivity to a certain target, such as: cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and the like. However, the medicines have the problems of single action target point, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.

Currently, two monoamine oxidase enzymes (Monoamine oxidases) have been identified and characterized in humans, including two subtypes MAO-A and MAO-B, which are primarily responsible for oxidative deamination of biogenic amines such as 5-hydroxytryptamine, dopamine, norepinephrine and phenethylamine, and monoamine neurotransmitters to regulate their concentration and metabolism in the brain and surrounding tissues. MAO-B is mainly distributed in the outer mitochondrial membrane of glial cells, takes Flavin Adenine Dinucleotide (FAD) as a coenzyme factor, and is a main enzyme for oxidative deamination of dopamine in the brain. In recent years, the research shows that the expression quantity of MAO-B in the brain of an AD or PD patient is abnormally increased, and the enzyme can destroy cholinergic neurons, promote the generation of Abeta plaque and neurofibrillary tangles and obviously reduce the content of dopamine in the brain; in addition, the MAO-B can produce H ₂O₂ at the same time of catalytic deamination, and the produced H ₂O₂ can produce hydroxyl free radicals with endogenous Cu ²⁺、Fe²⁺ plasma through Fenton reaction (Fenton reaction), and the hydroxyl free radicals can damage lipid, protein and nucleic acid, so that mitochondria function is disordered, and finally brain neuron cell death is caused. Therefore, the deamination of MAO-B can be inhibited, so that the content of dopamine in brain can be improved, and the effects of antioxidation stress and neuroprotection can be achieved by reducing the generation of free radicals and active oxygen; in addition, the inhibition of MAO-B has been found to increase the content of phenethylamine in the brain, which in turn stimulates dopamine release and inhibits dopamine reuptake. Thus, selective inhibitors of MAO-B have been found to be of great importance in the treatment and/or prevention of neurological related disorders.

In recent years, along with the continuous elucidation of the pathogenesis of neurodegenerative diseases, the occurrence and development of neurodegenerative diseases are found to have the characteristics of multi-mechanism and multi-factor actions, and the different mechanisms are mutually related and mutually influenced, so that a complex network regulation and control system in the occurrence and development process of the neurodegenerative diseases is formed. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of neurodegenerative diseases is a current necessary choice. Based on the above results, researchers have proposed a "multi-target targeted drug" strategy to develop anti-neurodegenerative disease drugs. By "multi-target drug" is meant a single chemical entity that acts on multiple targets in the disease network simultaneously, and the effects on each target can produce a synergistic effect such that the total effect is greater than the sum of the individual effects. The main differences of the multi-target medicine and multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between medicines and the toxic and side effect caused by the interaction, has uniform pharmacokinetic property, is convenient to use, and the like. Therefore, the development of the anti-neurodegenerative disease treatment drug with novel chemical structure, novel action mechanism, multi-target effect and low toxic and side effect is an important current direction.

Disclosure of Invention

The invention aims to disclose a phenol alkenyl phthalide pyrazolone compound (I).

The invention also aims to disclose a preparation method of the phenol alkenyl phthalazinone pyrazolone compound (I).

It is a further object of the present invention to disclose pharmaceutical compositions comprising such a phenol alkenylphthalazinone compound (I).

It is still another object of the present invention to disclose the use of the phenol alkenylphthalazinone pyrazolone compound (I) having a multi-target effect for the preparation of a medicament for the treatment and/or prevention of neurological related diseases, including, but not limited to, vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and neurological damage caused by brain trauma.

The chemical structural general formula of the phenol alkenyl phthalazinone pyrazolone compound (I) disclosed by the invention is as follows:

Wherein: x represents O, S or NH; r ₁ represents propargyl, C ₂～C₁₂ alkenyl, wherein the olefinic bond in the alkenyl is at any possible position of R ₁, but the 3-position of the phthalide core is a saturated carbon; r ₂ and R ₃ each independently represent H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃、CF₃O、R₄ CONH, CN or NR ₅R₆, these substituents being in any possible position on the benzene ring where the ortho-hydroxyphenyl group is located; r ₄ represents a C _1-4 alkyl group; r ₅ and R ₆ each independently represent H, C _1-4 alkyl; NR ₅R₆ also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; the compound is in R configuration, S configuration or any ratio mixture of R and S configuration; the term "halogen" refers to F, cl, br or I.

The phenol alkenyl phthalide pyrazolone compound (I) disclosed by the invention can be prepared by the following method: the corresponding 4-hydroxy benzopyran-2-ketone compound (1) is used as a starting material, and reacts with a racemized or chiral 6-hydrazino-3-substituted phthalide compound (2) in a solvent to obtain a phenol alkenyl phthalide pyrazolone compound (I); the reaction formula is as follows:

Wherein: x, R ₁、R₂ and R ₃ are defined as the chemical structural general formula of the phenol alkenyl phthalazinone compound (I).

For the above synthetic route, the specific preparation method is described as follows:

The solvents used in the reaction are: fatty alcohol C _1-6, fatty acid C _1-6, ester of fatty acid C _1-6 and fatty alcohol C _1-6, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene, xylene or chlorobenzene, preferably the solvent is: n, N-dimethylformamide, toluene, xylene or chlorobenzene; 4-hydroxybenzopyran-2-one compound (1): the molar feed ratio of the 6-hydrazino-3-substituted phthalide compound (2) is 1.0:1.0 to 5.0, preferably a molar feed ratio of 1.0:1.0 to 2.0; the reaction temperature is room temperature to 180 ℃, preferably 80 to 140 ℃; the reaction time is 1 to 72 hours, preferably 4 to 30 hours.

The starting materials of the present invention, 4-hydroxybenzopyran-2-one compound (1) and 6-hydrazino-3-substituted phthalide compound (2), can be prepared by techniques common in the art, including but not limited to the methods disclosed in the following documents ：1、K.A.Nolan,et al.J.Med.Chem.2009,52,7142-7156;2、X.Qiang,et al.Bioorg.Med.Chem.Lett.2017,27,718-722.

The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more phenolalkenylphthalein pyrazolones (I), which may further comprise one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that causes a biological or medical response to a tissue, system or animal targeted by a researcher or doctor; the term "composition" refers to a product formed by mixing more than one substance or component; the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances that carry or transport a chemical substance. The ideal proportion of the pharmaceutical composition provided by the invention is that the phenol alkenyl phthalazinone compound (I) is taken as an active ingredient to account for 2 to 99.5 percent of the total weight.

The phenol alkenyl phthalazinone compound (I) disclosed by the invention is subjected to the following biological activity screening:

(1) Inhibition activity of phenolalkenylphthalein pyrazolone compound (I) on monoamine oxidase B

Recombinant human MAO-B was formulated as 75. Mu.g/mL sample solution with 100mM potassium phosphate buffer pH 7.4. Adding 20 mu L of a compound solution to be detected into a black 96-well plate, uniformly mixing, incubating at 37 ℃ for 15min at a dark place, adding 200 mu M of an Amplex Red reagent, 2U/mL of horseradish peroxidase and 2mM of phenylmethylamine to initiate reaction, incubating at 37 ℃ for 20min, and measuring fluorescence emission intensity at 590nm by fixing excitation wavelength 545nm on a multifunctional enzyme-labeled instrument, wherein a potassium phosphate buffer solution is used as a blank instead of MAO-B; the inhibition rate of the compound for inhibiting monoamine oxidase is calculated as follows: 100- (IF _i)/(IF_c) x 100, where IF _i and IF _c are the difference between the fluorescence intensity in the presence and absence of inhibitor, respectively, and the blank fluorescence intensity. Each compound was assayed 3 replicate wells at a time and each set of experiments was independently repeated three times. Five to six concentrations of the compound are selected, the enzyme inhibition rate is measured, and the molar concentration at which 50% inhibition rate is obtained is the IC ₅₀ of the compound by linear regression of the negative logarithm of the molar concentration of the compound and the inhibition rate of the enzyme. The measurement result shows that the phenol alkenyl phthalazinone compounds (I) disclosed in the embodiment of the invention have remarkable inhibition effect on MAO-B, wherein IC ₅₀ is 0.06 mu M-23.2 mu M (for example, 0.18 mu M for the compounds 1-1-13, 0.91 mu M for the compounds 1-2-13 and 1.57 mu M for the compounds 1-3-13); further, the research on the structure-activity relationship shows that the inhibition activity of MAO-B of the corresponding compound is greatly reduced by replacing 'OH' on a benzene ring where an o-hydroxyphenyl group is positioned in the molecule of the phenol alkenyl phthalazinone compound (I) with 'H', and the IC ₅₀ values are all more than 30 mu M.

(2) Platelet aggregation inhibiting Activity of the phenol alkenyl phthalazinone Compounds (I)

Taking 3 male rabbits, carrying out local anesthesia by using lidocaine, separating the common carotid artery by operation to obtain blood, and taking 3.8 percent sodium citrate 1:9 anticoagulation, centrifugation at 500r/min for 10 min, preparation of Platelet Rich Plasma (PRP), centrifugation of the remainder at 3000r/min, preparation of Platelet Poor Plasma (PPP), and nephelometry for platelet aggregation. 240 mu L of PRP and 30 mu L of test drugs with different concentrations are added into a measuring tube, incubated for 5 minutes, 30 mu L of Adenosine Diphosphate (ADP) (the final concentration is 10 mu mol/L) is respectively taken as an inducer, and the maximum aggregation rate within 5 minutes is observed and recorded; the inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The measurement result shows that the phenol alkenyl phthalazinone compound (I) disclosed in the embodiment of the invention has remarkable inhibition effect on platelet aggregation induced by ADP, the inhibition rate of the compound (I) is 30.5-83.6% at the concentration of 33.0 mu M, and the inhibition rate of the compound (I) is more than 50.0% at the concentration of 100.0 mu M; whereas the inhibition rates of the positive control butylphthalide and aspirin at 33.0. Mu.M concentration were 9.3% and 12.5%, respectively.

(3) Antioxidant Activity of the phenol-based alkenylphthalazinone Compounds (I) (ORAC-FL method)

The determination is carried out by the method reported in reference (Qiang, x.m. et al, eur.j med.chem.2014,76, 314-331), namely: 6-hydroxy-2, 5,7, 8-tetramethylchromane-2-carboxylic acid (Trolox) was formulated as a 10-80. Mu. Mol/L solution with PBS buffer at pH7.4, fluorescein (fluoscein) was formulated as a 250nmol/L solution with PBS buffer at pH7.4, and 2,2' -azobisisobutylamidine dihydrochloride (AAPH) was formulated as a 40mmol/L solution with PBS buffer at pH7.4 prior to use. 50-10 mu mol/L of compound solution and fluorescein solution are added into a 96-well plate, the mixture is uniformly mixed, incubated for 15min at 37 ℃, AAPH solution is added to ensure that the total volume of each well is 200 mu L, the mixture is uniformly mixed, and the mixture is immediately placed into a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and the mixture is continuously measured for 90min at 485nm excitation wavelength and 535nm emission wavelength. The area under the fluorescence decay curve AUC is calculated, wherein the antioxidant activity result of the compound is expressed as the equivalent of Trolox by taking Trolox of 1-8 mu mol/L as a standard and taking a non-added sample to be detected as a blank, the calculation formula is ：[(AUC Sample-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration of Trolox/concentration of sample)],, 3 compound holes are measured each time for each compound, and each group of experiments are independently repeated three times. The measurement result shows that the antioxidant activity of the phenol alkenyl phthalazinone compound (I) disclosed in the embodiment of the invention is 0.96-3.6 times that of Trolox, which indicates that the compound has stronger antioxidant activity. Further researches show that the anti-oxidation activity of the corresponding compound is obviously reduced by replacing 'OH' on a benzene ring where an o-hydroxyphenyl group is positioned in the molecule of the phenol alkenyl phthalazinone compound (I) in the embodiment by 'H', and the anti-oxidation activity is reduced by at least 1.5-6.0 times, which indicates that 'OH' on the benzene ring where the o-hydroxyphenyl group is positioned has important influence on the anti-oxidation activity of the compound; in addition, the study also shows that the chiral center of the phenol alkenyl phthalazinone compound (I) has no influence on the antioxidant activity.

(4) Complexation of phenolalkenylphthalein pyrazolone compound (I) with metal ion

Dissolving CuCl ₂·2H₂O、ZnCl₂、FeSO₄、AlCl₃ and a compound to be tested with methanol to prepare a 75 mu mol/L solution, adding 100 mu L of the compound to be tested and 100 mu L of the metal ion solution into a 96-well plate, uniformly mixing, standing at room temperature for 30min, recording an ultraviolet absorption curve of the mixture in a range of 200-600nm on a Varioskan Flash Multimode Reader instrument, and observing the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the mixed solution of the metal ions and the compound to be tested by taking 100 mu L of the compound to be tested and 100 mu L of the methanol mixed solution as a reference. The measurement result shows that the phenol alkenyl phthalazinone compounds (I) disclosed in the embodiment of the invention show complexation effect on the metal ions; the OH on the benzene ring where the o-hydroxyphenyl is located in the structure is replaced by H, and the obtained corresponding compound has almost no complexation effect with the metal ions (the maximum absorption peak intensity of the mixed solution of the compound to be tested and the metal ions has no obvious change, and the maximum absorption peak has no red shift phenomenon). The study shows that the 'OH' on the benzene ring where the o-hydroxyphenyl is located has a significant effect on the metal ion complexation of the compound.

(5) Inhibitory Activity of the phenol-based alkenylphthalazinone Compounds (I) against neuroinflammation

(A) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity

Inoculating BV-2 cells in logarithmic growth phase into a cell suspension, placing the cell suspension into a 96-well plate, culturing in a 5% CO ₂ cell culture box at 37 ℃ for 24 hours, changing the cell suspension into 90 mu L of fresh culture solution without serum after the cell is attached, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30min, and simultaneously setting a blank control group at each concentration of 3 parallel wells; then, adding or not adding LPS, placing in a 37 ℃ and 5% CO ₂ cell incubator for continuous culture for 24 hours, adding MTT solution, incubating for 4 hours at 37 ℃, discarding supernatant, adding 200 mu L of DMSO solution into each hole, slightly oscillating for 10 minutes, measuring the OD value at 490nm by using an enzyme-labeling instrument, calculating the average value of the OD values measured by different concentrations of each sample, and calculating the cell survival rate according to the following companies: cell viability (%) = mean OD of dosing group/mean OD of control group x 100%. The test results show that all the phenolic alkenylphthalazinone compounds (I) disclosed in the examples of the invention show no cytotoxicity (inhibition less than < 10%) at concentrations not exceeding 25 μm.

(B) Effect of the phenol alkenyl phthalazinone Compounds (I) on LPS-induced release of NO by BV-2 cells

Inoculating BV-2 cells in logarithmic growth phase into a cell suspension, placing the cell suspension into a 96-well plate, culturing in a 5% CO ₂ cell culture box at 37 ℃ for 24 hours, changing the cell suspension into 90 mu L of fresh culture solution without serum after the cell is attached, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30min, and simultaneously setting a blank control group at each concentration of 3 parallel wells; then adding LPS (1.0 mug/ml) for stimulation, placing the mixture in a 37 ℃ and 5% CO ₂ cell culture box for continuous culture for 24 hours, taking cell culture supernatants of different treatment groups, adding an equal volume of Griess reagent I and an equal volume of Griess reagent II, reacting for 10 minutes at room temperature in a dark place, and measuring absorbance at 540nm to detect the NO level in the cell supernatant (the specific operation is carried out according to the instruction of a NO detection kit). Test results show that all the phenol alkenyl phthalazinone compounds (I) disclosed in the embodiment of the invention show strong inhibition effect on LPS-induced BV-2 cell NO generation in the concentration range of 0.5 mu M to 25 mu M (inhibition rate at the concentration of 5.0 mu M is more than 32.3%), and have obvious dose-effect relationship; the compound (I) has obvious anti-neuroinflammation activity.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.

EXAMPLE 1 preparation of phenol alkenyl phthalazinone compound (I)

The corresponding 4-hydroxybenzopyran-2-one compound (1) (2.0 mmol), 6-hydrazino-3-substituted phthalide compound (2) (3.0 mmol) and toluene (60 ml) were added into a reaction flask, followed by heating, refluxing and stirring for reaction for 4.0 to 24.0 hours (the progress of the reaction was followed by TLC); after the reaction is finished, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane-ethyl acetate=20:1v/v) to obtain the corresponding phenol alkenyl phthalazinone compound (I), the yield is 35.7% -66.5%, the chemical structures are confirmed by ¹H-NMR、¹³ C-NMR and ESI-MS, and the purity of the obtained target product is more than 96.0% by HPLC determination. The structure of the target object prepared by the general method is as follows:

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The ¹ H-NMR data for some of the compounds were as follows:

¹HNMR(DMSO-d₆):12.50(brs,1H),10.16(s,1H),8.24(dd,J₁＝8.4Hz,J₂＝2.4Hz,1H),8.17(s,1H),7.88(d,J＝8.4Hz,1H),7.29(d,J＝2.4Hz,1H),6.88-6.82(m,2H),6.25(s,1H),5.83(t,J＝8.4Hz,1H),3.76(s,3H),3.06(m,2H),2.83(s,1H);

¹HNMR(CDCl₃):9.44(s,1H),8.25(s,1H),8.13(d,J＝8.4Hz,1H),7.47(d,J＝9.4Hz,1H),6.94(s,2H),6.66(s,1H),5.75-5.65(m,1H),5.48(t,J＝6.0Hz,1H),5.15-5.09(m,2H),3.91(s,2H),3.74(s,3H),2.17-2.59(m,2H);

¹HNMR(CDCl₃):9.51(s,1H),8.30(s,1H),8.20(dd,J₁＝8.4 Hz,J₂＝2.0 Hz,1H),7.50(d,J＝8.4Hz,1H),7.03-6.97(m,2H),6.71(s,1H),5.84-5.74(m,1H),5.51-5.48(m,1H),5.01-4.93(m,2H),3.97(s,2H),3.80(s,3H),2.07-2.02(m,3H),1.84-1.73(m,1H),1.52-1.38(m,6H);

¹HNMR(CDCl₃):9.51(s,1H),8.31(s,1H),8.14(d,J＝8.4 Hz,1H),7.59(d,J＝8.4 Hz,1H),7.04-6.98(m,2H),6.73(s,1H),5.93-5.86(m,1H),5.25(s,1H),5.22-5.11(m,2H),3.97(s,2H),3.81(s,3H),1.28(s,3H),0.97(s,3H);

¹HNMR(DMSO-d₆):12.59(s,1H),10.46(s,1H),8.21(s,1H),8.19(s,1H),7.75(d,J＝8.0 Hz,1H),7.54(s,1H),7.02(d,J＝8.0 Hz,1H),6.82(d,J＝8.0 Hz,1H),6.14(s,1H),5.89-5.82(m,1H),5.55(s,1H),5.15-5.07(m,2H),2.27(s,3H),1.19(s,3H),0.99(s,3H);

¹HNMR(CDCl₃):9.84(s,1H),8.25(s,1H),8.08(d,J＝8.4 Hz,1H),7.53(d,J＝8.4 Hz,1H),7.34(t,J＝8.0 Hz,1H),7.18(s,1H),7.02(s,1H),6.92(t,J＝7.6 Hz,1H),5.86-5.79(m,1H),5.18(s,1H),5.15-5.04(m,2H),3.94(s,2H),1.21(s,3H),1.18(s,3H).

Claims

1. A phenol alkenyl phthalide pyrazolone compound is characterized in that the chemical structural general formula of the compound is shown as (I):

Wherein: x represents O, S or NH; r ₁ represents propargyl, C ₂～C₁₂ alkenyl, wherein the olefinic bond in the alkenyl is at any possible position of R ₁, but the 3-position of the phthalide core is a saturated carbon; r ₂ and R ₃ each independently represent H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃、CF₃O、R₄ CONH, CN or NR ₅R₆, these substituents being in any possible position on the benzene ring where the ortho-hydroxyphenyl group is located; r ₄ represents a C _1-4 alkyl group; r ₅ and R ₆ each independently represent H, C _1-4 alkyl; NR ₅R₆ also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; the term "halogen" refers to F, cl, br or I.

2. The phenolalkenylphthalein pyrazolone compound of claim 1, wherein R ₁ represents propargyl, allyl, 1-allyl hexyl, 1-allyl heptyl, 3-dimethyl-1-allyl.

3. The phenolalkenylphthalein pyrazolone compound of claim 1, characterized in that R ₂ and R ₃ each independently represent H, F, cl, br, methyl, methoxy, CF ₃、CF₃O、CH₃CONH、CN、NH₂、N(CH₃)₂, tetrahydropyrrolyl, morpholinyl or piperidinyl.

4. A process for the preparation of a phenolalkenylphthalein pyrazolone compound as claimed in any one of claims 1 to 3, wherein said compound is prepared by:

Wherein: x, R ₁、R₂ and R ₃ are defined as the chemical structural general formula of the phenol alkenyl phthalazinone compound (I);

the corresponding 4-hydroxy benzopyran-2-ketone compound (1) is used as a starting material, and reacts with a racemized or chiral 6-hydrazino-3-substituted phthalide compound (2) in a solvent to obtain the corresponding phenol alkenyl phthalide pyrazolone compound (I).

5. The method for preparing the phenol-based alkenylphthalazinone compound according to claim 4, wherein the solvent used in the reaction is: c _1-6 fatty alcohol, C _1-6 fatty acid, ester of C _1-6 fatty acid and C _1-6 fatty alcohol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene, xylene or chlorobenzene.

6. The method for preparing the phenol-based alkenylphthalazinone compound according to claim 4, wherein the 4-hydroxybenzopyran-2-one compound (1): the molar feed ratio of the 6-hydrazino-3-substituted phthalide compound (2) is 1.0:1.0 to 5.0.

7. The method for preparing the phenol alkenyl phthalazinone compound according to claim 4, wherein the reaction temperature is room temperature to 180 ℃; the reaction time is 1-72 hours.

8. A pharmaceutical composition comprising a phenolalkenylphthalein pyrazolone compound as claimed in any one of claims 1-3 in association with one or more pharmaceutically acceptable carriers or excipients.

9. Use of a phenolalkenylphthalein pyrazolone compound as claimed in any one of claims 1-3 in the manufacture of a medicament for the treatment and/or prophylaxis of neurological-related disorders of the type: vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with Lewy bodies, parkinson's disease, huntington's disease, HIV-associated dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.