CN117903092A - Dihydroxyphthalide compound and preparation method and application thereof - Google Patents
Dihydroxyphthalide compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN117903092A CN117903092A CN202311756935.8A CN202311756935A CN117903092A CN 117903092 A CN117903092 A CN 117903092A CN 202311756935 A CN202311756935 A CN 202311756935A CN 117903092 A CN117903092 A CN 117903092A
- Authority
- CN
- China
- Prior art keywords
- benzyl
- phenethyl
- dihydroxyphthalide
- compound
- allyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a dihydroxyphthalide compound (I) and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicines for treating and/or preventing diseases by resisting oxidative stress, inhibiting amyloid aggregation, metal ion complexation or resisting neuroinflammation, 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 stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a dihydroxyphthalide 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'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 cerebral 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. 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. Drugs currently approved 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, inappetence, frequent stool 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.
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 dihydroxyphthalide compound (I).
The invention also aims to disclose a preparation method of the dihydroxyphthalide compound (I).
It is a further object of the present invention to disclose pharmaceutical compositions comprising such dihydroxyphthalides (I).
It is still another object of the present invention to disclose the use of the dihydroxyphthalides (I) for the preparation of a medicament for the treatment and/or prophylaxis of neurological related disorders, 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 due to brain trauma.
The chemical structural general formula of the dihydroxyphthalide compound (I) provided by the invention is as follows:
wherein: a represents O, S, se or NR 1,R1 represents H, C 1~C6 alkyl; r represents a C 1~C8 alkyl group, Benzyl, substituted benzyl, phenethyl, substituted phenethyl; n represents 1 to 6; the "substituted benzyl" or "substituted phenethyl" refers to a benzyl or phenethyl group substituted on the benzene ring with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 alkyl, C 1-4 alkoxy, N (CH 3)2, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and cyano, wherein the compound is in R configuration, S configuration or a mixture of R configuration and S configuration in any proportion.
The dihydroxyphthalide compound (I) disclosed by the invention can be prepared by the following method, and the reaction formula is as follows:
wherein: the definition of A and R is the same as the chemical structural general formula of the dihydroxyphthalide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
Taking the corresponding trimethoxy phthalide compound (1) as a raw material, and selectively demethylating in the presence of hydrobromic acid and a solvent to obtain the corresponding dihydroxyphthalide compound (I); wherein, the solvent used in the reaction is: water, C 2-6 fatty acids, benzene, toluene or chlorobenzene; trimethoxyphthalide compound (1): the molar feed ratio of hydrogen bromide in hydrobromic acid is 1.0:3.0 to 100.0, preferably a molar feed ratio of 1.0:3.0 to 50.0; the reaction temperature is 10-160 ℃, preferably 20-130 ℃; the reaction time is 2 to 120 hours, preferably 5 to 24 hours.
The starting material of the present invention, trimethoxyphthalides (1), can be prepared by techniques common in the art, including but not limited to the methods disclosed in the following documents: reddy, S.R.et al.WO 2013102935.
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more dihydroxyphthalides (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 dihydroxyphthalide compound (I) is taken as an active ingredient and accounts for 2% -99.5% of the total weight.
The dihydroxyphthalide compound (I) disclosed by the invention is subjected to the following biological activity screening:
(1) Antioxidant Activity of dihydroxyphthalides (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 dihydroxyphthalide compound (I) disclosed in the embodiment of the invention is 2.23-3.46 times that of Trolox, which indicates that the compound has powerful antioxidant activity. Further, the research on the structure-activity relationship shows that the initial raw material trimethoxy phthalide compound (1) used in the embodiment of the invention has weaker antioxidant activity, and the activity is 0.28 to 0.80 times that of Trolox; and removing a methyl group on the phthalide nucleus of the trimethoxy phthalide compound (1), wherein the obtained corresponding dimethoxy phthalide compound has a certain antioxidant activity which is 0.96-2.08 times of Trolox but is weaker than that of the dihydroxy phthalide compound (I); the antioxidant activity of butylphthalide is 0.22 times that of Trolox. The above studies indicate that the presence of two phenolic hydroxyl groups in the molecule of the dihydroxyphthalide compound (I) is critical for enhancing the antioxidant activity of the compound.
(2) Inhibitory Activity of dihydroxyphthalides (I) on Abeta 1-42 self-aggregation
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: the pretreated Abeta 1-42 is prepared into stock solution by DMSO, and diluted to 50 mu M by PBS buffer solution of pH7.4 before use; the test compound was prepared as a 2.5mM stock solution with DMSO, diluted to the corresponding concentration with PBS buffer of pH7.4 before use, 20. Mu.L of Abeta 1-42 solution+20. Mu.L of test compound solution, 20. Mu.L of Abeta 1-42 solution+20. Mu.L of PBS buffer (containing 2% DMSO) were taken in a 96-well plate, incubated at 37℃for 24 hours, then 160. Mu.L of glycine-NaOH buffer (pH=8.5) containing 5. Mu.M thioflavin T was added, and immediately after shaking for 5 seconds, the fluorescence value was measured with a multifunctional microplate reader at 446nm excitation wavelength and 490nm emission wavelength; the fluorescence value of the Abeta 1-42 + compound to be tested is marked as IF i,Aβ1-42 + and the fluorescence value of the PBS buffer solution is marked as IF c, the fluorescence value of the PBS buffer solution only is marked as IF 0, and the inhibition rate of the compound to inhibit Abeta 1-42 from aggregating is as follows: 100- (IF i-IF0)/(IFc-IF0) 100; selecting five to six concentrations of the compound and determining the inhibition thereof; each concentration of each compound was repeated three times with curcumin as positive control. The measurement result shows that the dihydroxyphthalide compound (I) disclosed in the embodiment of the invention has remarkable inhibition activity on Abeta 1-42 self-aggregation, the inhibition rate of Abeta 1-42 self-aggregation is 75.0% -93.8% (the inhibition rate of curcumin is 41.2%) under the concentration of 25.0 mu M, such as: the inhibition ratios of the example compounds 1-3, 1-4, 1-5, 1-7 and 1-8 were 78.8%, 90.2%, 83.3%, 80.5% and 82.0%, respectively; the inhibition ratios of the example compounds 2 to 10, 2 to 11 and 2 to 18 were 81.8%, 83.6% and 89.5%, respectively, and the inhibition ratios of the example compounds 3 to 11, 3 to 18, 4 to 20 and 5 to 18 were 77.0%, 84.2%, 86.3% and 84.5%, respectively. Further structure-activity relationship researches show that the inhibition rate of the initial raw material trimethoxy phthalide compound (1), the corresponding dimethoxy phthalide compound obtained after removing one methyl group on the phthalide mother nucleus of the trimethoxy phthalide compound (1) and butylphthalide on Abeta 1-42 self aggregation is less than 40.0% at the concentration of 25.0 mu M.
(3) Determination of complexation of dihydroxyphthalides (I) with Metal ions
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 dihydroxyphthalide compound (I) disclosed in the embodiment of the invention shows complexation effect on the metal ions; the initial material trimethoxy phthalide compound (1) used in the embodiment of the invention has almost no complexation 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 two phenolic hydroxyl groups present in the molecule of the dihydroxyphthalide compound (I) have a significant effect on the metal ion complexation of the compound.
(4) Inhibitory Activity of dihydroxyphthalides (I) on 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 of the dihydroxyphthalides (I), the starting materials used-trimethoxyphthalides (1), butylphthalide and LPS disclosed in the examples of the present invention showed no cytotoxicity (inhibition rate < 10%) at a concentration of not more than 25. Mu.M.
(B) Effect of dihydroxyphthalides (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 for stimulation, placing the mixture in a 37 ℃ and 5% CO 2 cell culture incubator 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 (specific operation is carried out according to the instruction of a NO detection kit). The test result shows that all the dihydroxyphthalides (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 10 mu M (the inhibition rate at the concentration of 10.0 mu M is more than 68.0%), and have obvious dose-effect relationship; and the inhibition rate of butylphthalide at the concentration of 10.0 mu M is 45.5%. The study also shows that the initial raw material trimethoxyphthalide compound (1) used in the embodiment of the invention also has anti-neuroinflammation activity (the inhibition rate of LPS-induced BV-2 cell NO generation is 38.0% -59.5% at the concentration of 10.0 mu M).
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 general preparation of dihydroxyphthalides (I)
Trimethoxyphthalide compound (1) (4.0 mmol), hydrobromic acid (150.0 mmol) and acetic acid (20 ml) are added into a reaction bottle, and the mixture is heated, refluxed and stirred for reaction for 5 to 24 hours (the reaction progress is tracked by TLC); after the reaction, adjusting the pH of the solution to about 4.0 by sodium bicarbonate, extracting for three times by ethyl acetate (90 ml), washing an organic layer by saturated sodium chloride aqueous solution after combining, drying by anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether-acetone=3:1v/v), and obtaining a corresponding dihydroxyphthalide compound (I), wherein the yield is 35.3% -62.8%, and the chemical structure is confirmed by 1H-NMR、13 C-NMR, NOE and ESI-MS; the purity of the obtained target is greater than 96.0% as determined by HPLC. The structure of the target object prepared by the general method is as follows:
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1H-NMR、13 C-NMR and high resolution mass spectrum data for some compounds were as follows:
1HNMR(400MHz,CDCl3):6.46(s,1H),5.40(brs,2H),3.99(s,3H),2.18-1.99(m,1H),1.74-1.68(m,1H),1.42-1.29(m,4H),0.93(t,J=6.8Hz,3H);13CNMR(100MHz,CDCl3):171.8,153.7,142.5,141.9,132.8,105.7,96.1,82.4,56.7,34.6,26.8,22.4,13.9;HRMS(ESI)calcd for C13H17O5[M+H]+m/z:253.1071,found 253.1072;
1HNMR(400MHz,CDCl3):6.46(s,1H),5.39(brs,2H),3.99(s,3H),1.98(brs,1H),1.73(brs,1H),1.45-1.29(m,6H),0.89(t,J=6.8Hz,3H);13CNMR(100MHz,CDCl3):171.8,153.7,142.5,142.0,132.8,105.7,96.1,82.4,56.7,34.9,31.5,24.4,22.4,14.0;HRMS(ESI)calcd for C14H19O5[M+H]+m/z:267.1227,found 267.1224;
1HNMR(400MHz,CDCl3):6.46(s,1H),5.39(brs,2H),3.99(s,3H),2.18-1.97(m,1H),1.72-1.69(m,1H),1.43-1.29(m,8H),0.88(t,J=6.8Hz,3H);13CNMR(100MHz,CDCl3):171.8,153.7,142.5,142.0,132.8,105.7,96.1,82.4,56.7,34.9,31.6,29.0,24.7,22.5,14.0;HRMS(ESI)calcd for C15H21O5[M+H]+m/z:281.1384,found 281.1386.
Claims (10)
1. The dihydroxyphthalide compound is characterized in that the chemical structural general formula of the compound is shown as (I):
wherein: a represents O, S, se or NR 1,R1 represents H, C 1~C6 alkyl; r represents a C 1~C8 alkyl group, Benzyl, substituted benzyl, phenethyl, substituted phenethyl; n represents 1 to 6; the "substituted benzyl" or "substituted phenethyl" refers to a benzyl or phenethyl group substituted on the benzene ring with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 alkyl, C 1-4 alkoxy, N (CH 3)2, trifluoromethyl, trifluoromethoxy, amino, hydroxy, cyano).
2. The dihydroxyphthalide compound according to claim 1, wherein a represents O, R represents methyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, allyl, 1-cycloheptyl, 3-dimethyl-1-allyl, 2-methyl-2-allyl, propargyl, benzyl, phenethyl, (3-methoxy) benzyl, (4-methoxy) phenethyl, 4-fluorobenzyl, 4-fluorophenethyl, (4-dimethylamino) benzyl, (3-dimethylamino) phenethyl, (4-trifluoromethoxy) benzyl, (4-trifluoromethoxy) phenethyl, (4-methyl) benzyl, (4-trifluoromethyl) phenethyl, (4-cyano) benzyl, (3, 4-difluoro) benzyl.
3. The dihydroxyphthalide compound according to claim 1, wherein a represents S, R represents methyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, allyl, 1-cycloheptyl, 3-dimethyl-1-allyl, 2-methyl-2-allyl, propargyl, benzyl, phenethyl, (3-methoxy) benzyl, (4-methoxy) phenethyl, 4-fluorobenzyl, 4-fluorophenethyl, (4-dimethylamino) benzyl, (3-dimethylamino) phenethyl, (4-trifluoromethoxy) benzyl, (4-trifluoromethoxy) phenethyl, (4-methyl) benzyl, (4-trifluoromethyl) phenethyl, (4-cyano) benzyl, (3, 4-difluoro) benzyl.
4. The dihydroxyphthalide compound according to claim 1, wherein a represents Se, R represents methyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, allyl, 1-cycloheptyl, 3-dimethyl-1-allyl, 2-methyl-2-allyl, propargyl, benzyl, phenethyl, (3-methoxy) benzyl, (4-methoxy) phenethyl, 4-fluorobenzyl, 4-fluorophenethyl, (4-dimethylamino) benzyl, (3-dimethylamino) phenethyl, (4-trifluoromethoxy) benzyl, (4-trifluoromethoxy) phenethyl, (4-methyl) benzyl, (4-trifluoromethyl) phenethyl, (4-cyano) benzyl, (3, 4-difluoro) benzyl.
5. A dihydroxyphthalide compound according to claim 1, wherein A represents NH or NCH 3, R represents methyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, allyl, 1-cycloheptyl, 3-dimethyl-1-allyl, 2-methyl-2-allyl, propargyl, benzyl, phenethyl, (3-methoxy) benzyl, (4-methoxy) phenethyl, 4-fluorobenzyl, 4-fluorophenethyl, (4-dimethylamino) benzyl, (3-dimethylamino) phenethyl, (4-trifluoromethoxy) benzyl, (4-trifluoromethoxy) phenethyl, (4-methyl) benzyl, (4-trifluoromethyl) phenethyl, (4-cyano) benzyl, (3, 4-difluoro) benzyl.
6. A process for the preparation of a dihydroxyphthalide compound according to any one of claims 1 to 5, wherein the compound is prepared by:
wherein: the definition of A and R is the same as the chemical structural general formula of the dihydroxyphthalide compound (I);
The corresponding trimethoxy phthalide compound (1) is used as a raw material, and the corresponding dihydroxyphthalide compound (I) is obtained by selectively demethylating in the presence of hydrobromic acid and a solvent.
7. The method for preparing the dihydroxyphthalide compound according to claim 6, wherein the solvent used in the reaction is: water, C 2-6 fatty acids, benzene, toluene or chlorobenzene; trimethoxyphthalide compound (1): the molar feed ratio of hydrogen bromide in hydrobromic acid is 1.0:3.0 to 100.0; the reaction temperature is 10-160 ℃; the reaction time is 2 to 120 hours.
8. A pharmaceutical composition comprising a dihydroxyphthalide compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers or excipients.
9. Use of a dihydroxyphthalide compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and/or prophylaxis of diseases by anti-oxidative stress, inhibition of amyloid aggregation, metal ion complexation or anti-neuroinflammation.
10. Use of a dihydroxyphthalide compound according to claim 9, wherein the disease is: 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 or nerve damage caused by brain trauma.
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