A piperidine derivative, pharmaceutical composition, and use and method of preparation thereof

Abstract

This application relates to the field of medicinal chemistry, specifically disclosing a piperidine derivative, a pharmaceutical composition, its uses, and a method for preparation. The piperidine derivative has the structure of general formula (I). This piperidine derivative can significantly improve the learning and memory abilities of Aβ-induced Alzheimer's disease model rats and effectively reduce acetylcholinesterase activity in brain tissue, providing a potential candidate for the development of novel Alzheimer's disease treatments.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and more specifically, to a piperidine derivative, a pharmaceutical composition, and its uses and preparation methods. Background Technology

[0002] Alzheimer's disease (AD), a progressive neurodegenerative disease, is clinically characterized by memory impairment, cognitive decline, and behavioral abnormalities, severely impacting patients' quality of life and social function. Its pathogenesis is complex, involving multiple pathological processes such as β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, cholinergic system dysfunction, oxidative stress, and neuroinflammation. Among these, the decline in central cholinergic system function is closely related to cognitive impairment; abnormally elevated acetylcholinesterase (AChE) activity leads to decreased acetylcholine levels, further impairing learning and memory function.

[0003] In current drug development, piperidine compounds are used in the structural design of central nervous system drugs due to their moderate basicity, good conformational flexibility, and superior central nervous system exposure characteristics. However, most known piperidine derivatives have not shown ideal effects in improving cognitive function and regulating the cholinergic system, especially in animal models where significant and stable recovery of cognitive function is difficult to achieve. Furthermore, these compounds have limited ability to inhibit AChE activity and cannot effectively restore cholinergic neurotransmission function, thus limiting their application in the treatment of Alzheimer's disease.

[0004] Although structurally similar piperidine derivatives have been reported (e.g., carebastine), their pharmacological activity is mediocre, showing a significant gap compared to positive control drugs. Therefore, there is an urgent need in the field to develop a class of novel piperidine derivatives with rationally optimized structures, significant cognitive-improving effects, and potent AChE-inhibiting activity to provide more effective treatment strategies for Alzheimer's disease. Summary of the Invention

[0005] To address the aforementioned technical problems, this application provides a piperidine derivative, a pharmaceutical composition, its uses, and a method for preparation. This application, through specific functional group modification of piperidine compounds, enables the resulting compounds to significantly improve learning and memory function and effectively regulate cholinergic system function, providing a novel drug candidate for the clinical treatment of Alzheimer's disease.

[0006] In a first aspect, this application provides a piperidine derivative having the general formula (I), or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:

[0007]

[0008] (I)

[0009] in,

[0010] R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl groups;

[0011] R3 is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, and halogen;

[0012] n is an integer selected from 1 to 8, and when n is 3, R1 and R2 cannot be methyl at the same time.

[0013] Furthermore, in the above general formula (I):

[0014] R1 and R2 are each independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl;

[0015] The C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more of the following substituents: deuterium, halogen, hydroxyl, cyano, amino, or nitro;

[0016] Furthermore, in the above general formula (I):

[0017] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl group.

[0018] Furthermore, in the above general formula (I):

[0019] R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl groups;

[0020] R3 is hydrogen;

[0021] n is an integer selected from 1 to 6, and when n is 3, R1 and R2 cannot be methyl at the same time.

[0022] Furthermore, the above-mentioned piperidine derivatives are selected from the following compounds:

[0023]

[0024]

[0025] Furthermore, the pharmaceutically acceptable salts mentioned above include acetates, ascorbic acid salts, benzoates, benzenesulfonates, citrates, fumarates, hydrochlorides, hydrobroms, maleates, methanesulfonates, sulfates, hydrogen sulfates, nitrates, oxalates, phosphates, succinates, alkali metal salts, ammonium salts, basic amino acid salts, or pyridine salts.

[0026] Furthermore, the hydrogen in the above compound structure can be replaced by one or more deuterium atoms.

[0027] Secondly, this application provides the use of the above-mentioned piperidine derivative, or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of neurodegenerative diseases.

[0028] Furthermore, the aforementioned prevention of neurodegenerative diseases includes at least one of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), prefrontal dementia, multiple system atrophy, progressive supranuclear palsy, progressive ALS, and progressive muscular dystrophy.

[0029] Thirdly, this application provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, comprising a therapeutically effective amount of the aforementioned piperidine derivative, or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0030] Fourthly, this application provides a method for preparing the piperidine derivative having the above-mentioned general formula (I), comprising:

[0031] (a) In the presence of a Lewis acid catalyst, to produce an acid with the formula X-(CH2) n The haloacyl halide of -C(O)Cl undergoes an acylation reaction with methyl phenyl acetate to give intermediate a, where X is chlorine or bromine and n is an integer selected from 1 to 8;

[0032] (b) The intermediate a is subjected to a nucleophilic substitution reaction with 4-(diphenylmethoxy)piperidine under basic conditions to obtain ester intermediate b;

[0033] (c) Under alkaline conditions, the ester intermediate b is hydrolyzed to convert the terminal methyl ester group into a carboxyl group to obtain a piperidine derivative having the general formula (I).

[0034] In summary, this application has the following beneficial effects:

[0035] Based on in-depth research and structure-activity relationship analysis of the piperidine core structure, this application designed and synthesized a series of novel piperidine derivatives. Surprisingly, even some compounds structurally similar to existing analogs (such as carebastine) exhibited significantly superior pharmacological activity compared to existing analogs, and even comparable to clinical positive control drugs. Experimental results showed that the compounds of this application (such as in Example 3) significantly shortened the latency period, increased the number of loops, and markedly improved the learning and memory abilities of AD model rats in a β-amyloid protein-induced Alzheimer's disease animal model. Simultaneously, these compounds effectively inhibited the abnormal increase of AChE in hippocampal tissue and restored cholinergic system function. This phenomenon of "significant performance improvement through structural fine-tuning" highlights the non-obviousness of the structural design and pharmacological effects of the compounds in this application, providing a new and important direction for drug development in Alzheimer's disease. Detailed Implementation

[0036] The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Specific conditions not specified in the examples shall be carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0037] Unless otherwise stated, the scientific and technical terms used herein should have the meanings commonly understood by those skilled in the art. However, the following terms have the following definitions:

[0038] "alkyl" refers to a saturated aliphatic hydrocarbon group or linker, preferably a straight-chain or branched group with 1 to 6 carbon atoms.

[0039] "Cycloalkyl" is an all-carbon monocyclic structure, in which the ring may contain one or more double bonds, but such rings do not have a complete conjugated π-electron system. "C1-C6 cycloalkyl" refers to cyclic groups composed of 3 to 6 carbon atoms, such as (but not limited to): cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, cyclohexane, cyclohexadienyl, etc.

[0040] "Alkoxy" refers to alkyl-O-, including C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups are (but are not limited to): methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy, etc.

[0041] "Halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" includes a branched or straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms and being substituted with one or more halogens. One or more halogens may be independently selected from fluorine, chlorine, bromine, and iodine.

[0042] "Pharmaceutically acceptable salts" refer to organic or inorganic salts whose active molecules are toxicologically compatible. Examples of such salts include, but are not limited to: sulfates, citrates, acetates, oxalates, chlorine bromide, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinate, lactates, salicylates, citrates, tartrates, oleates, tannins, and pantothenic acid.

[0043] Salts, tartrates, ascorbic acid salts, succinates. Maleates, gentianates, fumarates, gluconates, glucurons, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts.

[0044] "Effective amount" refers to the amount of a drug or agent (i.e., the compound of the present invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who has not received the aforementioned amount, results in improved treatment, cure, prevention, or reduction of a disease, symptom, or side effect, or a slower rate of progression of a disease or symptom. Effective amounts may be administered, applied, or dosed in one or more administrations and are not intended to be limited to a particular formulation or route of administration. The term also includes effective amounts within its scope that enhance normal physiological function.

[0045] "Pharmaceutically acceptable carriers" refer to one or more excipients, stabilizers, fillers, binders, humectants, disintegrants, solution retarders, absorption enhancers, wetting agents, absorbents, lubricants, colorants, diluents, emulsifiers, preservatives, solubilizers, suspending agents, etc. These carriers are suitable for administration to subjects at doses and concentrations that are commensurate with a reasonable benefit / risk ratio and without undue adverse side effects (such as toxicity, irritation, and allergic reactions). Examples of acceptable carriers for pharmaceuticals include water, citrate or phosphate buffers, starch, lactose, sucrose, glucose, mannitol, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, glycerol, agar, calcium carbonate, alginic acid, sodium carbonate, paraffin, quaternary ammonium compounds, cetyl alcohol, glyceryl monostearate, kaolin and bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oil, tetrahydrofuran alcohol, fatty acid esters, isostearyl sulfoxide, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum hydroxide, tragacanth gum and mixtures thereof, and other ingredients well known to those skilled in the art.

[0046] The structure of the compound in this application was determined by nuclear magnetic resonance (NMR). 1 Determined by ¹H NMR or LC-MS.

[0047] The LC-MS instrument was an Agilent G6120B (compatible with an Agilent 1260 LC-MS system); nuclear magnetic resonance (¹H NMR) shifts (δ) were given in parts per million (ppm); the solvent was DMSO-d6 or CDCl3; the internal standard was tetramethylsilane (TMS); and chemical shifts were expressed in 10⁻¹⁰ ppm. -6 (ppm) is given as the unit.

[0048] The term "room temperature" refers to a temperature between 10 and 35°C.

[0049] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0050] Example 1

[0051] This embodiment provides a piperidine derivative: 2-[4-(3-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}propionyl)phenyl]-2-methylpropionic acid (compound 1), the specific synthetic route of which is shown below:

[0052]

[0053] Step 1: Synthesis of Compound 1a

[0054] In a 100 ml reaction flask, 8.0 g (0.06 mol) of anhydrous aluminum trichloride was added, followed by 25 ml of dichloromethane. The mixture was cooled to 0 °C, and 5.08 g (0.04 mol) of 3-chloropropionyl chloride was added dropwise. After the addition was complete, the mixture was kept at 25 °C for 15 minutes, then cooled to 0 °C, and 5.35 g (0.03 mol) of methyl 2,2-dimethylphenylacetate / 25 ml dichloromethane solution was added dropwise. The mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction solution was slowly added dropwise to 100 ml of ice water. After the addition was complete, 10 ml of hydrochloric acid was added, and the mixture was stirred for 10 minutes. The mixture separated into layers. The aqueous layer was extracted twice with 80 ml × 2 dichloromethane. The organic layers were combined and washed successively with 50 ml of saturated sodium bicarbonate solution and 50 ml of water. The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then separated by reverse-phase chromatography to obtain 2.75 g of intermediate 1a, with a yield of 34%.

[0055] Step 2: Synthesis of Compound 1b

[0056] In a 100 ml single-necked flask, 2.15 g (7.08 mmol) of 4-(diphenylmethoxy)piperidine hydrochloride, 20 ml of DMAC, 4.50 g (21.2 mmol) of K₃PO₄, and 118 mg (0.71 mmol) of KI were added and stirred until heated to 100 °C. 2.28 g (8.48 mmol) of compound 1a was dissolved in 5 ml of DMAC and slowly added dropwise to the reaction mixture. The mixture was kept at this temperature for 4–6 hours, and TLC was used to confirm the complete reaction of the starting material. The mixture was cooled to room temperature, and isopropyl acetate and water were added. The mixture was stirred until the layers separated. The aqueous phase was extracted again with isopropyl acetate. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and filtered through a silica gel column to give 1.48 g of compound 1b, with a yield of 42%.

[0057] ESI-MS: m / z =500.3(M+H) + .

[0058] Step 3: Synthesis of Compound 1

[0059] Compound 1b (500 mg, 1 mmol), 10 ml methanol, and 4 ml 10% NaOH were added to a 25 ml three-necked flask. The mixture was heated to 60 °C and reacted for 2 hours. The reaction proceeded completely by TLC. After the reaction was complete, the mixture was cooled to room temperature, concentrated to dryness, and EA was added. The pH was adjusted to 2-3 with hydrochloric acid. The mixture was allowed to separate into layers, washed once with water, and the organic phase was concentrated to dryness. The organic phase was then purified by reverse-phase chromatography to obtain 280 mg of compound 1, with a yield of 58% and a purity of 95.8%.

[0060] ESI-MS: m / z = 486.3(M+H) + .

[0061] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m, 12H), 5.48(s, 1H), 3.73 (m, 1H), 3.08–3.06 (t, 2H), 2.83–2.81 (t, 2H), 2.77–2.43 (m,4H), 1.93–1.72 (m, 4H), 1.58 (s, 6H).

[0062] Example 2

[0063] This embodiment provides a piperidine derivative: 2-[4-(2-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}acetyl)phenyl]-2-methylpropionic acid (compound 2).

[0064]

[0065] Compound 2, with a purity of 95.7%, can be prepared by replacing 3-chloropropionyl chloride with chloroacetyl chloride according to the preparation method in Example 1.

[0066] ESI-MS: m / z = 472.2(M+H) + .

[0067] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m, 12H), 5.48(s, 1H), 3.73 (m, 1H), 3.52 (s, 2H), 2.87–2.51 (m, 4H), 1.94–1.78 (m, 4H), 1.58 (s, 6H).

[0068] Example 3

[0069] This embodiment provides a piperidine derivative: 2-[4-(5-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-ylidenepentyl)phenyl]-2-methylpropionic acid (compound 3).

[0070]

[0071] Compound 3, with a purity of 96.0%, can be prepared by replacing 3-chloropropionyl chloride with 5-chlorovaleryl chloride according to the preparation method in Example 1.

[0072] ESI-MS: m / z = 514.3(M+H) + .

[0073] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m, 12H), 5.48(s, 1H), 3.73 (m, 1H), 2.98–2.95 (t, 2H), 2.77–2.50 (m, 4H), 2.45–2.44 (t,2H), 1.96–1.75 (m, 4H), 1.62–1.59 (m, 4H), 1.58 (s, 6H).

[0074] Example 4

[0075] This embodiment provides a piperidine derivative: [4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-ylidene)phenyl]acetic acid (compound 4).

[0076]

[0077] Following the preparation method in Example 1, 3-chloropropionyl chloride was replaced with 4-chlorobutyryl chloride, and methyl 2,2-dimethylphenylacetate was replaced with methyl phenylacetate to obtain compound 4 with a purity of 96.2%.

[0078] ESI-MS: m / z = 472.2(M+H) + .

[0079] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.55 (m, 2H), 7.37–7.29 (m, 10H), 5.48 (s, 1H), 3.73 (m, 1H), 3.59 (s, 2H), 2.96–2.93 (t, 2H), 2.77–2.71 (m, 2H), 2.58–2.50 (m, 4H), 1.96–1.75 (m, 6H).

[0080] Example 5

[0081] This embodiment provides the preparation of a piperidine derivative: 2-[4-(7-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylideheptyl)phenyl]-2-methylpropionic acid (compound 5).

[0082]

[0083] Compound 5, with a purity of 96.0%, can be prepared by replacing 3-chloropropionyl chloride with 7-bromoheptyl chloride according to the preparation method in Example 1.

[0084] ESI-MS: m / z = 542.3(M+H) + .

[0085] 1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m, 12H), 5.48(s, 1H), 3.73 (m, 1H), 2.90–2.87 (t, 2H), 2.77–2.71 (m, 2H), 2.55–2.50 (m,2H), 2.42–2.39 (t, 2H), 1.96–1.90 (m, 2H), 1.82–1.75 (m, 2H), 1.70–1.63 (m,2H), 1.56 (s, 6H), 1.52–1.47 (m, 2H), 1.40–1.28 (m, 4H).

[0086] Example 6

[0087] This embodiment provides a piperidine derivative: [4-(5-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-ylidenepentyl)phenyl]acetic acid (compound 6).

[0088]

[0089] Following the preparation method in Example 1, 3-chloropropionyl chloride was replaced with 5-chlorovaleryl chloride, and methyl 2,2-dimethylphenylacetate was replaced with methyl phenylacetate to obtain compound 6 with a purity of 95.7%.

[0090] ESI-MS: m / z = 486.3(M+H) + .

[0091] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.55 (m, 2H), 7.37–7.29 (m, 10H), 5.48 (s, 1H), 3.73 (m, 1H), 3.59 (s, 2H), 2.98 – 2.95 (t, 2H),2.77 – 2.71 (m, 2H), 2.55 – 2.50 (m, 2H), 2.46 – 2.44 (t, 2H), 1.96 – 1.90(m,2H), 1.82 – 1.75 (m, 2H), 1.67 – 1.53 (m, 4H).

[0092] Example 7

[0093] This embodiment provides a piperidine derivative: 2-[4-(6-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-ylidenehexyl)phenyl]-2-methylpropionic acid (compound 7).

[0094]

[0095] Compound 7, with a purity of 95.1%, can be prepared by replacing 3-chloropropionyl chloride with 6-chlorohexanoyl chloride according to the preparation method in Example 1.

[0096] ESI-MS: m / z = 528.3(M+H) + .

[0097] 1 H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m, 12H), 5.48(s, 1H), 3.73 (m, 1H), 2.90–2.87 (t, 2H), 2.77–2.50 (m, 4H), 2.42–2.39 (t,2H), 1.96–1.90 (m, 2H), 1.82–1.75 (m, 2H), 1.67–1.60 (m, 2H), 1.58 (s, 6H), 1.54–1.49 (m, 2H), 1.42–1.36 (m, 2H).

[0098] Example 8

[0099] This embodiment provides a piperidine derivative: 2-[4-(7-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-ylidene-heptyl)phenyl]-propionic acid (compound 8).

[0100]

[0101] Following the preparation method in Example 1, 3-chloropropionyl chloride was replaced with 7-bromoheptyl chloride, and methyl 2,2-dimethylphenylacetate was replaced with methyl phenylacetate to obtain compound 8 with a purity of 95.8%.

[0102] ESI-MS: m / z = 514.3 (M+H) + .

[0103] 1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.55 (m, 2H), 7.37–7.29 (m, 10H), 5.48 (s, 1H), 3.73 (m, 1H), 3.59 (s, 2H), 2.90 – 2.87 (t, 2H),2.77 – 2.71 (m, 2H), 2.55 – 2.50 (m, 2H), 2.42 – 2.39 (t, 2H), 1.96 – 1.90(m,2H), 1.82 – 1.75 (m, 2H), 1.69 – 1.63 (m, 2H), 1.52 – 1.47 (m, 2H), 1.40 –1.29 (m, 4H).

[0104] Comparative Example 1: Commercially available doperazine hydrochloride tablets.

[0105] .

[0106] Comparative Example 2: Carebastine

[0107] .

[0108] Comparative Example 3: Compound 9

[0109] The comparative compound was prepared according to the preparation method in Example 2 of patent CN1571784A, with a purity of 97.3%.

[0110]

[0111] ESI-MS: m / z = 478.2 (M+H) + .

[0112] 1 H NMR(CDCl3): δ1.62-1.90(m, 8H), 2.14-2.22(m, 2H), 2.39(t, J=14.9Hz,2H), 3.45-3.51(m, 1H), 4.3(t, J=12.7Hz, 2H), 5.53(s, 1H), 7.27-7.37(m, 10H), 7.41(d, J=8.5Hz, 2H), 7.97(d, J=8.5Hz, 2H).

[0113] Experimental Example

[0114] This experimental example aims to evaluate the effects of the compounds in this application series on the impairment of learning and memory abilities and the improvement of the cholinergic system in β-amyloid (Aβ)-induced Alzheimer's disease (AD) model rats.

[0115] 1. Establish a β-amyloid (Aβ)-induced Alzheimer's disease (AD) model.

[0116] (1) Experimental animals: SD rats, acclimatized for one week.

[0117] (2) Aβ 25-35 Preparation of oligomers: Aβ 25-35 Pre-chill hexafluoroisopropanol (HFIP) and other medications on an ice pack, per 1 mg Aβ 25-35 Add 220 μl of HFIP and operate on ice. Cap the tube and incubate at room temperature for 60 min to allow Aβ to develop. 25-35 Completely dissolve the Aβ25-35. Place the dissolved Aβ25-35 back on ice for 10 min, then in a fume hood to evaporate overnight. The next day, ventilate the fume hood for 2 h. A flaky precipitate will be visible. Add dimethyl sulfoxide to the centrifuge tubes in a clean bench, mix thoroughly, and then add phenol red-free DMEM / F12 medium to each tube. Incubate at 4°C for 24 h. The following day, centrifuge at 4°C and 12000 r / min for 10 min. Transfer the supernatant to new tubes, aliquot, and store at -20°C at a concentration of 100 μmol / L. Identify Aβ using atomic force microscopy. 25-35 Oligomer.

[0118] (3) Model establishment: Rats were anesthetized by intraperitoneal injection and fixed on a stereotactic instrument. The CA1 region of the hippocampus was located (3.0 mm posterior to the anterior fontanelle, 2.0 mm lateral to the midline, and 2.9 mm subdurally). After drilling open the skull, Aβ was slowly injected over 5 min using a microsyringe. 25-35 Inject 5 μl of oligomer, leave the needle in for 25 minutes after injection, then slowly withdraw it. Repeat the same procedure on the other side, suture the skin to prevent infection, and complete the establishment of the AD animal model.

[0119] 2. Dosing regimen

[0120] Normal rats were used as the blank control group. The AD model rats were randomly divided into the model control group, the example treatment group and the comparative treatment group, with 8 rats in each group.

[0121] Comparative Example 1 was administered commercially available doperidine hydrochloride tablets 3 mg / kg orally via gavage (positive control). The blank control group and the model control group were administered an equal volume of physiological saline via gavage. Comparative Example 2 and Comparative Example 3 were administered carebastine and compound 8 in equimolar amounts as in Comparative Example 1, once daily for 7 consecutive days.

[0122] 3. Effects of the compound on learning and memory abilities in AD model rats

[0123] Seven days after administration, learning and memory abilities were assessed using the Morris water maze, including a navigation experiment (recording latency) and a spatial exploration experiment (number of loops). The results are shown in Table 1.

[0124] Table 1: Morris water maze test results for rats in each group (Mean±SD)

[0125]

[0126] As can be seen from Table 1:

[0127] The piperidine derivatives provided in this application demonstrate significantly superior effects compared to existing analogues and comparable to positive control drugs in improving learning and memory abilities in Alzheimer's disease model rats. Aβ 25-35 After induction, the learning and memory abilities of rats in the model group were significantly impaired, manifested by a significantly prolonged latency and a significantly reduced number of ring-passing attempts. The positive control drug, Comparative Example 1 (doperazine), showed a clear improvement effect, with a latency of 35.63±3.38 s and a recovery in the number of ring-passing attempts to 4.75±1.04. However, the structurally similar comparative examples 2 (carebastine) and 3 showed limited improvement effects and were statistically significantly worse than Comparative Example 1 (P<0.01), indicating that the existing analogues are insufficiently effective at the behavioral level.

[0128] In contrast, Example 3, which stands out in this application, exhibited excellent results approaching those of the control group, with a latency of only 32.13 ± 1.64 s and a recovery in the number of circumcisions to 5.13 ± 0.64. Its behavioral indicators were not only significantly better than all comparative examples and Example 1 (P < 0.01), but also showed no statistical difference from the positive control. Furthermore, Examples 4 to 7 also showed cognitive improvement capabilities comparable to the positive control.

[0129] 4. Effects of the compound on AChE activity in brain tissue of AD model rats

[0130] After the behavioral tests, the rats were euthanized and the hippocampus tissue was quickly dissected. The AChE activity in the hippocampus tissue was determined by spectrophotometry and expressed as micromoles of hydrolyzed substrate per gram of tissue per hour (μmol / h / g). The results are shown in Table 2.

[0131] Table 2: Acetylcholinesterase (AChE) activity in hippocampal tissue of rats in each group (Mean±SD)

[0132]

[0133] As can be seen from Table 2:

[0134] The compound presented in this application demonstrated a significant advantage in inhibiting abnormally elevated acetylcholinesterase (AChE) activity in the brains of AD model rats. The AChE activity in the model group was significantly higher than that in the control group, indicating damage to the cholinergic system. The positive control drug (Comparative Example 1) effectively inhibited this activity, restoring it to near-normal levels. However, Comparative Examples 2 and 3, which have similar structures, although showing some inhibitory effect, still exhibited significantly higher activity than the positive control group, indicating that their inhibitory ability on AChE was limited and failed to effectively correct cholinergic dysfunction.

[0135] In contrast, the AChE activity of Example 3 of this application has recovered to a level comparable to the blank group, significantly better than all comparative examples and Example 1, and the effect is comparable to the positive control. Examples 4 to 7 also showed good inhibitory activity, all approaching or reaching the level of the positive control.

[0136] In summary, based on in-depth research and structure-activity relationship analysis of the piperidine core structure, this application designed and synthesized a series of novel piperidine derivatives. Surprisingly, even though some compounds are structurally similar to existing analogues (such as Comparative Example 2), they exhibit significantly superior pharmacological activity compared to existing analogues, and even comparable to clinical positive control drugs. Experimental results show that the compounds of this application (such as Example 3) significantly shortened latency and increased the number of ring passes in the Morris water maze behavioral test, significantly improving the learning and memory abilities of AD model rats; simultaneously, these compounds effectively inhibited the abnormal increase of AChE in hippocampal tissue, restoring cholinergic system function. This phenomenon of "significant performance improvement through structural fine-tuning" highlights the non-obviousness of the structural design and pharmacological effects of the compounds in this application, providing a new and important direction for drug development in Alzheimer's disease.

[0137] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A piperidine derivative having the general formula (I), or a pharmaceutically acceptable salt thereof: （I） The piperidine derivatives of general formula (I) are selected from the following compounds:

2. The piperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts include acetates, ascorbic acid salts, benzoates, benzenesulfonates, citrates, fumarates, hydrochlorides, hydrobroms, maleates, methanesulfonates, sulfates, hydrogen sulfates, nitrates, oxalates, phosphates, succinates, alkali metal salts, ammonium salts, basic amino acid salts, or pyridine salts.

3. Use of a piperidine derivative or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 in the preparation of a medicament for the prevention or treatment of Alzheimer's disease.

4. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, characterized in that, It comprises a therapeutically effective amount of the piperidine derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

5. A method for preparing a piperidine derivative having general formula (I) as described in claim 1 or 2, characterized in that, It includes: (a) In the presence of a Lewis acid catalyst, to produce an acid with the formula X-(CH2) n The haloacyl halide of -C(O)Cl undergoes an acylation reaction with methyl phenyl acetate to give intermediate a, where X is chlorine or bromine and n is an integer selected from 1 to 8; (b) The intermediate a is subjected to a nucleophilic substitution reaction with 4-(diphenylmethoxy)piperidine under basic conditions to obtain ester intermediate b; (c) Under alkaline conditions, the ester intermediate b is hydrolyzed to convert the terminal methyl ester group into a carboxyl group to obtain a piperidine derivative having the general formula (I).

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