Piperidinylalkyldihydroxyphthalidin compounds, processes for their preparation and uses thereof

Abstract

This invention discloses a class of piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts, their preparation methods, pharmaceutical compositions, and their use in the preparation of medicaments for treating and / or preventing diseases by means of anti-oxidative stress, inhibition of amyloid aggregation, metal ion complexation, or anti-neuroinflammatory effects, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, 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 traumatic brain injury;

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a class of piperidine alkyl dihydroxyphthalides (I) and their pharmaceutically acceptable salts, their preparation methods, pharmaceutical compositions, and their use in the preparation of drugs for the treatment and / or prevention of neurological diseases, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, 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 traumatic brain injury. Background Technology

[0002] Neurodegenerative diseases are a general term for diseases caused by chronic, progressive degeneration of central nervous system tissues. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Their pathogenesis is closely related to oxidative stress, neuroinflammation, and related damage. Oxidative stress is mediated by reactive oxygen species (ROS) free radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. Under normal physiological conditions, ROS production levels are in dynamic equilibrium with the body's antioxidant capacity. When ROS production exceeds the cellular antioxidant capacity, oxidative stress occurs. The brain is particularly sensitive to oxidative stress, thereby inducing various neurological diseases. Other studies have found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by traumatic brain injury are also closely related to oxidative stress and neuroinflammation in the body.

[0003] Vascular dementia (VD) is a clinical syndrome characterized by intellectual and cognitive impairment caused by various types of cerebrovascular diseases, including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease. Due to its complex pathogenesis, there are currently no drugs that can halt the progression of vascular dementia; clinical treatment focuses on improving cerebral blood circulation, brain metabolism, and enhancing brain nutrition.

[0004] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment and memory loss. Its incidence is rising annually, making it the third most prevalent disease after cardiovascular disease and cancer. With the accelerating aging of the global population, its incidence is showing a significant upward trend. It is estimated that more than 50 million people worldwide currently suffer from dementia, and the total cost of its treatment and care exceeded US$1 trillion in 2018. This number is projected to increase to 152 million by 2050. Because AD clinically manifests as a decline in memory, orientation, thinking, and judgment, as well as reduced daily living abilities and even abnormal mental and behavioral symptoms, patient care is challenging, placing a heavy burden on society and families. Currently approved drugs for treating mild / moderate AD include acetylcholinesterase (AChE) inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists for treating severe AD. However, clinical use has shown that while these drugs can alleviate Alzheimer's disease (AD) symptoms by increasing acetylcholine levels or inhibiting the excitatory toxicity of excitatory amino acids, they cannot effectively stop or reverse the disease progression. Furthermore, they can cause serious side effects such as hallucinations, confusion, dizziness, nausea, liver toxicity, loss of appetite, and frequent bowel movements, resulting in unsatisfactory long-term efficacy. Therefore, there is an urgent clinical need to develop novel AD treatments that can both improve AD symptoms and alter the disease progression.

[0005] Alzheimer's disease (AD) is caused by multiple factors and has a complex pathogenesis, which is not yet fully understood. However, studies have shown that decreased acetylcholine levels in the brain, excessive production and deposition of β-amyloid protein, platelet aggregation in cerebral blood vessels, metal ion metabolism disorders, and calcium deficiency are contributing factors. 2+ Multiple factors play important roles in the pathogenesis of Alzheimer's disease (AD), including imbalance, neurofibrillary tangles caused by tau-protein hyperphosphorylation, hyperactive glutamate receptors, oxidative stress leading to large amounts of reactive oxygen species (ROS) and free radicals, and neuroinflammatory responses. To address these pathogenic factors, researchers have employed the traditional "one drug, one target" drug design strategy, discovering numerous drugs with high activity and selectivity for specific targets, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. However, these drugs suffer from limitations such as single-target action, numerous toxic side effects during clinical use, and poor long-term efficacy in AD patients.

[0006] In recent years, with the continuous elucidation of the pathogenesis of neurodegenerative diseases, it has been discovered that the occurrence and development of neurodegenerative diseases are characterized by multiple mechanisms and factors, with different mechanisms interconnected and influencing each other, forming a complex network regulatory system in the occurrence and development of these diseases. Clearly, developing therapeutic drugs that can simultaneously act on multiple stages of the pathological process of neurodegenerative diseases is an inevitable choice. Based on these findings, researchers have proposed a "multi-target-guided drug" strategy for developing drugs against neurodegenerative diseases. A "multi-target drug" refers to a single chemical entity that simultaneously acts on multiple targets in the disease network, producing a synergistic effect on each target, making the total effect greater than the sum of the individual effects. The main differences between multi-target drugs and multi-drug combinations or compound drugs are: reduced dosage, improved therapeutic efficacy, avoidance of drug interactions and resulting toxic side effects, uniform pharmacokinetic characteristics, and ease of use. Therefore, developing anti-neurodegenerative disease therapeutic drugs with novel chemical structures, novel mechanisms of action, multi-target effects, and low toxicity is an important current direction. Summary of the Invention

[0007] The purpose of this invention is to disclose a class of piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts.

[0008] Another object of the present invention is to disclose a method for preparing the piperidine alkyl dihydroxyphthalide compound (I) and its pharmaceutically acceptable salt.

[0009] Another object of the present invention is to disclose pharmaceutical compositions comprising such piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts.

[0010] Another objective of this invention is to disclose that the piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts have multi-target effects and can be used in the preparation of drugs for the treatment and / or prevention of neurological diseases, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, 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 traumatic brain injury.

[0011] The general chemical structural formula of the piperidine alkyl dihydroxyphthalide compound (I) disclosed in this invention is as follows:

[0012]

[0013] In the formula: A represents O or S; n represents 1-6; R represents H, C1-C8 alkyl, 2-pyridinemethyl, 3-pyridinemethyl, 4-pyridinemethyl, benzyl, or substituted benzyl; the "substituted benzyl" refers to a benzyl group on the benzene ring that is substituted by 1-4 groups selected from the following group: F, Cl, Br, I, C 1-4 Alkyl, C 1-4 Alkoxy, NHCOCH3, N(CH3)2, trifluoromethyl; the compound is in the R configuration, S configuration, or any mixture of the R and S configurations in any proportion.

[0014] The piperidine alkyl dihydroxyphthalide compound (I) disclosed in this invention can be prepared by the following method, and its reaction formula is as follows:

[0015]

[0016] In the formula: n, A and R are defined in the same way as the general chemical structural formula of piperidine alkyl dihydroxyphthalide compounds (I).

[0017] The specific preparation method for the above synthetic route is described below:

[0018] Using the corresponding piperidine alkyl trimethoxyphthalide compound (1) as a starting material, selective demethylation in the presence of hydrobromic acid and a solvent yields the corresponding piperidine alkyl dihydroxyphthalide compound (I); wherein the solvent used in the reaction is: water, C 2-6 Fatty acids, benzene, toluene or chlorobenzene; piperidine alkyl trimethoxyphthalide compounds (1): the molar ratio of hydrogen bromide in hydrobromic acid is 1.0:3.0 to 120.0, preferably 1.0:4.0 to 60.0; the reaction temperature is 20℃ to 160℃, preferably 30℃ to 130℃; the reaction time is 2 to 96 hours, preferably 3 to 22 hours.

[0019] The piperidine alkyl dihydroxyphthalide compound (I) obtained by the above method can be reacted with any suitable acid to prepare its pharmaceutically acceptable salt by conventional salt-forming methods, wherein the acid is: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aminosulfonic acid, C 1-6 Fatty carboxylic acids (such as formic acid, acetic acid, propionic acid, etc.), trifluoroacetic acid, stearic acid, acetic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Alkyl sulfonic acids (such as methanesulfonic acid, ethyl sulfonic acid, etc.), camphor sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, or 1,4-butanedisulfonic acid.

[0020] The starting material of this invention—piperidine alkyl trimethoxyphthalide compound (1)—can be prepared using techniques common in the art, including but not limited to the methods disclosed in the following documents: 1. Reddy, SR et al. WO 2013102935; 2. Deng Yong et al. CN 201810285403.3; 3. Li, L. et al. Bioorg. Med. Chem. 2020, 28, 115400.

[0021] The pharmaceutical compositions disclosed in this invention comprise therapeutically effective amounts of one or more piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts, and may further contain one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of drug or agent that elicits a biological or pharmaceutical response in a tissue, system, or animal targeted by an investigator or physician; the "composition" refers to a product obtained by mixing one or more substances or components; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance, which carries or transports a chemical substance. Ideally, the pharmaceutical compositions provided by this invention contain piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts as active ingredients in an amount ranging from 2% to 99.5% by weight.

[0022] The piperidine alkyl dihydroxyphthalide compounds (I) and their pharmaceutically acceptable salts disclosed in this invention were subjected to the following bioactivity screening:

[0023] (1) Antioxidant activity of piperidine alkyl dihydroxyphthalide compounds (I) (ORAC-FL method)

[0024] The determination was performed according to the method reported in the literature (Qiang, XMet al.Eur.J Med.Chem.2014,76,314-331), namely: 6-hydroxy-2,5,7,8-tetramethyltryptane-2-carboxylic acid (Trolox) was prepared into a 10-80 μmol / L solution with PBS buffer at pH 7.4; fluorescein was prepared into a 250 nmol / L solution with PBS buffer at pH 7.4; and 2,2′-azobisisobutylamidine dihydrochloride (AAPH) was prepared into a 40 mmol / L solution with PBS buffer at pH 7.4 before use. Add 50-10 μmol / L of the compound solution and fluorescein solution to a 96-well plate, mix well, incubate at 37°C for 15 min, add AAPH solution to make the total volume of each well 200 μL, mix well, and immediately place in a Varioskan Flash Multimode Reader (ThermoScientific) instrument for continuous measurement at an excitation wavelength of 485 nm and an emission wavelength of 535 nm for 90 min. Calculate the area under the fluorescence decay curve (AUC), using 1-8 μmol / L Trolox as the standard and no sample as the blank. The antioxidant activity of the compound is expressed as the equivalent of Trolox, calculated using the formula: [(AUC Sample - AUC blank) / (AUC Trolox - AUC blank)] × [(concentration of Trolox / concentration of sample)]. Each compound was measured in triplicate, and each experiment was independently repeated three times. The results showed that the antioxidant activity of the piperidine alkyl dihydroxyphthalide compound (I) disclosed in the embodiments of the present invention was 2.30 to 3.28 times that of Trolox, indicating that this type of compound has strong antioxidant activity. Further structure-activity relationship studies revealed that the starting material used in the embodiments of the present invention—piperidine alkyl trimethoxyphthalide compound (1)—had weak antioxidant activity, which was 0.25 to 0.86 times that of Trolox; while the corresponding piperidine alkyl dimethoxyphthalide compound obtained by removing one methyl group from the phthalide core of piperidine alkyl trimethoxyphthalide compound (1) had certain antioxidant activity, which was 0.90 to 1.98 times that of Trolox, but weaker than that of piperidine alkyl dihydroxyphthalide compound (I); the antioxidant activity of butylphthalide was 0.25 times that of Trolox. The above studies indicate that the two phenolic hydroxyl groups on the phthalide core of the piperidine alkyl dihydroxyphthalide compound (I) molecule are crucial for enhancing the antioxidant activity of the compound.

[0025] (2) Piperidine alkyl dihydroxyphthalides (I) on Aβ 1-42 Inhibitory activity of self-aggregation

[0026] The determination was performed according to the method reported in the literature (Qiang, XMet al.Eur.J Med.Chem.2014,76,314-331), namely: pretreated Aβ 1-42 Prepare a stock solution using DMSO, and dilute to 50 μM with PBS buffer (pH 7.4) before use. Prepare a 2.5 mM stock solution of the analyte using DMSO, and dilute to the appropriate concentration with PBS buffer (pH 7.4) before use. Take 20 μL of Aβ... 1-42 Solution + 20 μL of the analyte solution, 20 μL of Aβ 1-42 Add 20 μL of PBS buffer (containing 2% DMSO) to a 96-well plate and incubate at 37°C for 24 h. Then add 160 μL of 50 mM glycine-NaOH buffer (pH = 8.5) containing 5 μM thioflavone T, shake for 5 s, and immediately measure the fluorescence value using a multi-functional microplate reader at an excitation wavelength of 446 nm and an emission wavelength of 490 nm. Aβ 1-42 +The fluorescence value of the test compound is denoted as IF. i , Aβ 1-42 The fluorescence value of +PBS buffer is denoted as IF. c The fluorescence value containing only PBS buffer is recorded as IF0, and the compound inhibits Aβ. 1-42 The inhibition rate of self-aggregation is: 100 - (IF) i -IF0) / (IF c -IF0)*100; Select five to six concentrations of the compound and determine its inhibition rate; Repeat the test three times for each compound at each concentration, with curcumin as a positive control. The results showed that the piperidine alkyl dihydroxyphthalide compounds (I) disclosed in the embodiments of the present invention all exhibited significant inhibitory activity against the self-aggregation of Aβ1-42. At a concentration of 25.0 μM, the inhibition rates against the self-aggregation of Aβ1-42 ranged from 76.2% to 95.5% (the inhibition rate of curcumin was 41.8%). For example, the inhibition rates of compounds 1-3, 1-16, 1-17, 2-3, 2-16, and 4-12 were 81.2%, 93.7%, 92.0%, 82.8%, 95.5%, and 90.3%, respectively; and the inhibition rates of compounds 5-3, 5-15, 6-3, 6-16, and 8-18 were 78.8%, 86.0%, 80.2%, 91.6%, and 78.3%, respectively. Further structure-activity relationship studies revealed that the starting material used in the embodiments of the present invention—piperidinyl trimethoxyphthalide compound (1), the corresponding piperidyl dimethoxyphthalide compound obtained after removing a methyl group from the phthalide core of piperidyl trimethoxyphthalide compound (1), and butylphthalide all had an inhibition rate of less than 45.0% on the self-aggregation of Aβ1-42 at a concentration of 25.0 μM.

[0027] (3) Determination of the complexation reaction between piperidine alkyl dihydroxyphthalide compounds (I) and metal ions

[0028] CuCl2·2H2O, ZnCl2, FeSO4, AlCl3, and the test compound were dissolved in methanol to prepare a 75 μmol / L solution. 100 μL of the test compound solution and 100 μL of the metal ion solution were added to a 96-well plate, mixed, and allowed to stand at room temperature for 30 min. The UV absorption curves of the mixture in the 200-600 nm range were recorded using a Varioskan Flash Multimode Reader. A mixture of 100 μL of the test compound solution and 100 μL of methanol was used as a control to observe the red shift of the maximum absorption peak and the intensity of the maximum absorption peak. The results showed that the piperidine alkyl dihydroxyphthalide compound (I) disclosed in the embodiments of this invention exhibited a complexing effect on the above-mentioned metal ions; while the starting material used in the embodiments of this invention—piperidine alkyl trimethoxyphthalide compound (1)—had almost no complexing effect with the above-mentioned metal ions (the intensity of the maximum absorption peak of the mixture of the test compound and the metal ion showed no significant change, and there was no red shift of the maximum absorption peak). This study shows that the two phenolic hydroxyl groups on the phthalide core of the piperidine alkyl dihydroxyphthalide compound (I) have a significant effect on the metal ion complexation of the compound.

[0029] (4) Inhibitory activity of piperidine alkyl dihydroxyphthalide compounds (I) on neuroinflammation; Effects of compound (a) and lipopolysaccharide (LPS) on BV-2 cell activity.

[0030] Logarithmic growth phase BV-2 cells were prepared into cell suspensions and seeded into 96-well plates. The plates were incubated at 37°C in a 5% CO2 incubator for 24 hours until cell attachment. Then, 90 μL of serum-free fresh culture medium was added, and 10 μL of each concentration of the test compound was added for pre-incubation for 30 minutes. Three parallel wells were used for each concentration, with a blank control group included. LPS was added or not added, and the plates were incubated at 37°C in a 5% CO2 incubator for another 24 hours. MTT solution was added, and the plates were incubated at 37°C for 4 hours. The supernatant was discarded, and 200 μL of DMSO solution was added to each well. After gentle shaking for 10 minutes, the OD value was measured at 490 nm using a microplate reader. The mean OD value of each test sample at different concentrations was calculated, and cell viability was calculated as follows: Cell viability (%) = Mean OD value of the drug group / Mean OD value of the control group × 100%. Test results show that all piperidine alkyl dihydroxyphthalide compounds (I) disclosed in the embodiments of the present invention, the starting material used—piperidine alkyl trimethoxyphthalide compound (1), and butylphthalide did not show cytotoxicity (inhibition rate less than 10%) at a concentration not exceeding 25 μM.

[0031] (b) Effect of piperidine alkyl dihydroxyphthalide (I) on LPS-induced NO release from BV-2 cells

[0032] Log-phase BV-2 cells were prepared into a cell suspension and seeded into 96-well plates. The plates were incubated at 37°C in a 5% CO2 incubator for 24 hours until cell attachment. The medium was then replaced with 90 μL of serum-free fresh culture medium. 10 μL of each concentration of the test compound was added for pre-incubation for 30 minutes, with three parallel wells per concentration. A blank control group was also included. LPS stimulation was then added, and the plates were incubated at 37°C in a 5% CO2 incubator for another 24 hours. The cell culture supernatant from each treatment group was collected, and equal volumes of Griess reagent I and Griess reagent II were added. The reaction was carried out at room temperature in the dark for 10 minutes. The absorbance was measured at 540 nm to detect the NO level in the cell supernatant (the specific procedure was performed according to the NO detection kit instructions). Test results showed that all piperidine alkyl dihydroxyphthalide compounds (I) disclosed in the embodiments of the present invention exhibited strong inhibitory effects on LPS-induced NO production in BV-2 cells within the concentration range of 0.5 μM to 10 μM (inhibition rates all exceeded 65.0% at a concentration of 10.0 μM), and showed a clear dose-response relationship; while butylphthalide showed an inhibition rate of 45.5% at a concentration of 10.0 μM. The study also found that the starting material used in the embodiments of the present invention—piperidine alkyl trimethoxyphthalide compound (1)—also had anti-neuroinflammatory activity (inhibition rate on LPS-induced NO production in BV-2 cells at a concentration of 10.0 μM ranged from 33.6% to 57.2%). Detailed Implementation

[0033] The present invention will be further described through the following embodiments; however, the scope of the present invention is not limited to the following embodiments. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from its spirit and scope.

[0034] Example 1: General method for preparing piperidine alkyl dihydroxyphthalide compounds (I)

[0035] Piperidinyl trimethoxyphthalide compound (1) (2.0 mmol), hydrobromic acid (100.0 mmol), and acetic acid (25 mL) were added to a reaction flask and the mixture was heated to reflux and stirred for 3–22 hours (the reaction progress was monitored by TLC). After the reaction, the pH of the solution was adjusted to alkaline with sodium bicarbonate, and the mixture was extracted three times with ethyl acetate (90 mL). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether-acetone = 5:1 v / v) to give the corresponding piperidinyl dihydroxyphthalide compound (I) in yield of 28.0%–53.6%. The chemical structures of the compounds were determined by chromatography. 1H-NMR, 13 The results were confirmed by C-NMR, NOE, and ESI-MS; the purity of the obtained target compounds was greater than 96.0% as determined by HPLC; the structures of the target compounds prepared by the above general method are as follows:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] Example 2: General method for preparing salts of piperidine alkyl dihydroxyphthalide compounds (I) with acids

[0043] 2.0 mmol of piperidine alkyl dihydroxyphthalide compound (I) obtained according to Example 1 above and 20 ml of ethanol were added to a reaction flask. After stirring evenly, 4.0 mmol of the corresponding acid was added. The mixture was stirred at room temperature for 25 minutes, and the solvent was removed by vacuum distillation. The residue was purified to obtain the salt of piperidine alkyl dihydroxyphthalide compound (I). Its chemical structure was determined by... 1 Confirmed by HNMR and ESI-MS.

Claims

1. A class of piperidine alkyl dihydroxyphthalides and their pharmaceutically acceptable salts, characterized in that... The general chemical structural formula of this type of compound is shown in (I): In the formula: A represents O or S; n represents 1-6; R represents H, C1-C8 alkyl, 2-pyridinemethyl, 3-pyridinemethyl, 4-pyridinemethyl, benzyl, or substituted benzyl; the "substituted benzyl" refers to a benzyl group on the benzene ring that is substituted by 1-4 groups selected from the following group: F, Cl, Br, I, C 1-4 Alkyl, C 1-4 Alkoxy, NHCOCH3, N(CH3)2, trifluoromethyl; the compound is in the R configuration, S configuration, or any mixture of the R and S configurations in any proportion.

2. The piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in claim 1, characterized in that... A represents O, n represents 1-6; R represents methyl, ethyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, (2-methyl)benzyl, (4-methyl)benzyl, (4-trifluoromethyl)benzyl, (2-methoxy)benzyl, (4-methoxy)benzyl, (2-dimethylamino)benzyl, (4-dimethylamino)benzyl, (4-acetamido)benzyl, 2-pyridinemethyl, 3-pyridinemethyl, 4-pyridinemethyl.

3. The piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in claim 1, characterized in that... A represents S, n represents 1-6; R represents methyl, ethyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, (2-methyl)benzyl, (4-methyl)benzyl, (4-trifluoromethyl)benzyl, (2-methoxy)benzyl, (4-methoxy)benzyl, (2-dimethylamino)benzyl, (4-dimethylamino)benzyl, 2-pyridinemethyl, 3-pyridinemethyl, 4-pyridinemethyl.

4. The piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in any one of claims 1-3, characterized in that... The pharmaceutically acceptable salts mentioned are those of piperidine alkyl dihydroxyphthalides and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aminosulfonic acid, C 1-6 Fatty acids, trifluoroacetic acid, stearic acid, tartaric acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Salts of alkyl sulfonic acids, camphor sulfonic acids, naphthalene sulfonic acids, benzene sulfonic acids, p-toluene sulfonic acids, or 1,4-butanedisulfonic acids.

5. The method for preparing the piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in any one of claims 1-4, characterized in that... The compound was prepared by the following method: In the formula: n, A and R are defined in the same way as the general chemical structural formula of piperidine alkyl dihydroxyphthalide compounds (I); Using the corresponding piperidine alkyl trimethoxyphthalide compound (1) as a raw material, selective demethylation is performed in the presence of hydrobromic acid and solvent to obtain the corresponding piperidine alkyl dihydroxyphthalide compound (I); then, a pharmaceutically acceptable salt can be prepared by conventional salting with an acid.

6. The method for preparing the piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in claim 5, characterized in that... The solvents used in the reaction are: water and C. 2-6 Fatty acids, benzene, toluene or chlorobenzene; piperidine alkyl trimethoxyphthalide compounds (1): the molar ratio of hydrogen bromide in hydrobromic acid is 1.0:3.0~120.0; the reaction temperature is 20℃~160℃; the reaction time is 2~96 hours.

7. A class of pharmaceutical compositions, characterized in that... It comprises a piperidine alkyl dihydroxyphthalide compound as described in any one of claims 1-4, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of the piperidine alkyl dihydroxyphthalide compounds and pharmaceutically acceptable salts thereof as described in any one of claims 1-4 in the preparation of medicaments for the treatment and / or prevention of diseases by means of anti-oxidative stress, inhibition of amyloid aggregation, metal ion complexation or anti-neuroinflammatory effects.

9. The use of the piperidine alkyl dihydroxyphthalide compound and its pharmaceutically acceptable salt as described in claim 8, characterized in that... The diseases mentioned are: vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, or nerve damage caused by traumatic brain injury.

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