Piperidine derivatives, pharmaceutical compositions and their uses for neurodegenerative diseases

Abstract

This application relates to the field of medicinal chemistry, specifically disclosing a piperidine derivative, a pharmaceutical composition, and its uses for neurodegenerative diseases. The piperidine derivative has the structure of general formula (I). In vivo experiments have demonstrated that these compounds effectively improve learning and memory impairment in β-amyloid-induced Alzheimer's disease model rats, significantly shortening escape latency and increasing the number of loops in the Morris water maze test. Their behavioral improvement effect is significantly superior to cascarastin and comparable to the positive control drug. Simultaneously, this series of compounds significantly inhibits abnormally elevated acetylcholinesterase activity in the hippocampus of model rats, exhibiting excellent regulatory effects on cholinergic system function and demonstrating a synergistic effect of cognitive improvement and regulation of key pathological processes. The compounds of this invention provide more promising drug candidates for the treatment of Alzheimer's disease.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and more specifically, to a piperidine derivative for neurodegenerative diseases, a pharmaceutical composition, and the use thereof. Background Technology

[0002] Alzheimer's disease (AD) is a central nervous system degenerative disease characterized by progressive cognitive decline, accounting for the vast majority of dementia cases in the elderly. Its pathological mechanisms are complex, involving multiple factors such as β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and cholinergic system dysfunction. Among these, cholinergic neurological deficits are considered one of the core factors leading to learning and memory impairment. Abnormally elevated acetylcholinesterase (AChE) activity exacerbates the breakdown of acetylcholine, thereby weakening synaptic transmission efficiency and affecting cognitive function.

[0003] In current drug development, piperidine structures are frequently used in the design of drugs for the treatment of neurodegenerative diseases due to their good brain penetration and potential effects on central targets. However, most piperidine derivatives reported so far have not shown ideal effects in improving learning and memory impairments and regulating the cholinergic system. Specifically, they exhibit limited cognitive and behavioral improvement in animal models, insufficient inhibitory activity against AChE, or insignificant protective effects against Aβ-induced neurological damage, thus making it difficult to achieve ideal therapeutic levels in comprehensive treatment.

[0004] Carlisle, a piperidine compound known to possess certain neuroprotective activities, has been reported to improve behavior and regulate cholinergic function in AD model animals. However, its efficacy still lags behind existing clinically proven drugs, limiting its further development and application. Therefore, there is an urgent need in this field to provide a novel class of piperidine compounds with novel structures and significant advantages in improving learning and memory abilities and regulating cholinergic system function, in order to overcome the limitations of current technologies in terms of insufficient efficacy and limited comprehensive therapeutic potential. Summary of the Invention

[0005] To address the aforementioned technical problems, this application provides a piperidine derivative, a pharmaceutical composition, and its uses for neurodegenerative diseases. Through systematic structural modification and activity screening, this application unexpectedly discovered a series of new compounds structurally similar to casartine but possessing significantly superior activity. This discovery provides new technical solutions and experimental evidence for the application of these compounds in the development of drugs for the treatment of Alzheimer's disease.

[0006] The technical solution adopted in this application is as follows:

[0007] In a first aspect, this application provides a piperidine derivative having the general formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0008]

[0009] (I)

[0010] in,

[0011] R1 and R2 are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, alkoxy, aryl and heteroaryl groups may optionally be substituted by one or more of the following substituents: deuterium, halogen, hydroxyl, cyano, amino or nitro.

[0012] R3 is selected from aryl, heteroaryl, aralkyl, or heteroaryl; wherein the aryl, heteroaryl, aralkyl, or heteroaryl group may optionally be substituted by one or more of the following substituents: deuterium, alkyl, alkoxy, halogen, hydroxyl, cyano, or nitro.

[0013] R4 is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, or halogen;

[0014] n is an integer selected from 1 to 8.

[0015] Furthermore, in the above formula (I):

[0016] R1 and R2 are each independently selected from hydrogen and C. 1-3 Alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, aryl, or heteroaryl;

[0017] R3 is selected from aryl, heteroaryl, aralkyl, or heteroaryl; wherein the aryl, heteroaryl, aralkyl, or heteroaryl group may optionally be substituted by one or more of the following substituents: deuterium, C 1-3 Alkyl, C 1-3 Alkyl or halogen;

[0018] R4 is selected from hydrogen, C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy;

[0019] n is an integer selected from 1 to 4.

[0020] Furthermore, in the above formula (I):

[0021] R1 and R2 are each independently selected from hydrogen or methyl;

[0022] R3 is selected from substituted or unsubstituted benzyl or biphenylmethyl;

[0023] R4 is selected from hydrogen;

[0024] n is selected from 3.

[0025] Furthermore, the above-mentioned piperidine derivatives are selected from the following compounds:

[0026]

[0027]

[0028] Furthermore, the hydrogen in the above-mentioned piperidine derivative structure is replaced by one or more deuterium atoms.

[0029] Furthermore, pharmaceutically acceptable salts of the above-mentioned compounds include acetates, ascorbic acid salts, benzoates, benzenesulfonates, citrates, fumarates, hydrochlorides, hydrobroms, maleates, methanesulfonates, sulfates, hydrogen sulfates, nitrates, oxalates, phosphates, or succinates; preferably hydrochlorides, hydrobroms, methanesulfonates, sulfates, or hydrogen sulfates; more preferably hydrochlorides.

[0030] Secondly, this application provides a pharmaceutical composition for 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.

[0031] Furthermore, the above composition is formulated for oral, injectable, parenteral, or nasal administration.

[0032] Thirdly, this application provides the use of the above-mentioned piperidine derivative, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the preparation of a medicament for the prevention or treatment of neurodegenerative diseases.

[0033] Furthermore, the aforementioned neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), prefrontal dementia, multiple system atrophy, progressive supranuclear palsy, progressive ALS, or progressive muscular dystrophy.

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

[0035] This invention provides a series of compounds that significantly improve learning and memory abilities in a β-amyloid-induced Alzheimer's disease animal model and effectively reduce acetylcholinesterase activity in brain tissue, demonstrating good cognitive function improvement and regulatory effects on the cholinergic system. This series of compounds not only significantly outperforms carestine in improving learning and memory behavior, but also exhibits a more pronounced regulatory effect on the cholinergic system, with overall efficacy comparable to commonly used positive control drugs. This discovery provides a new class of candidate compounds with higher clinical translational value for the treatment of 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] The structure of the compound in this application was determined by nuclear magnetic resonance (NMR). 1 Determined by ¹H NMR or LC-MS.

[0039] The liquid chromatography-mass spectrometry (LC-MS) system 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 10⁻⁶ ppm. -6 (ppm) is given as the unit.

[0040] The term "room temperature" refers to a temperature between 10 and 35°C.

[0041] 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.

[0042] Example 1

[0043] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-methylpropionate benzyl ester (compound 1), the specific synthetic route of which is shown below:

[0044]

[0045] The synthesis method is as follows:

[0046] Carestine (2.00 g, 4.0 mmol) and tetrahydrofuran (20 ml) were added to a 100 ml single-necked flask. Oxaloyl chloride (0.76 g, 6.0 mmol) was added to the reaction solvent, and two drops of DMF solvent were added dropwise. The resulting mixture was stirred at room temperature for more than 3 h. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in 20 ml of tetrahydrofuran solvent. The mixture was cooled in an ice-water bath, and then benzyl alcohol (0.52 g, 4.8 mmol) and triethylamine (0.49 g, 4.8 mmol) were added to the reaction system sequentially. The reaction mixture was stirred at room temperature overnight, then quenched with water, and the layers were separated by stirring with ethyl acetate. The aqueous phase was extracted again with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase preparative separation to give 1.25 g of compound 1, with a yield of 53% and a purity of 95.1%.

[0047] ESI-MS: m / z =590.3(M+H) + .

[0048] 1 H NMR (400 MHz, CDCl3) δ:7.89 – 7.83 (m, 2H), 7.45 – 7.39 (m, 2H), 7.39 – 7.25 (m, 15H), 5.64 (s, 1H), 5.13 (s, 2H), 3.84 – 3.81 (m, 1H), 2.95(t, 2H), 2.77 – 2.71 (m, 2H), 2.62 – 2.47 (m, 4H), 2.00 – 1.84 (m, 4H), 1.82– 1.75 (m, 2H), 1.58 (s, 6H).

[0049] Example 2

[0050] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-methylpropionic acid-(4-methoxyphenyl)methyl ester (compound 2), the specific synthetic route of which is shown below:

[0051]

[0052] Following the preparation method in Example 1, by replacing benzyl alcohol with p-methoxybenzyl alcohol, compound 2 with a purity of 96.4% can be obtained.

[0053] ESI-MS: m / z = 620.3(M+H) + .

[0054] 1 H NMR (400 MHz, CDCl3) δ: 7.89 – 7.83 (m, 2H), 7.45 – 7.39 (m, 2H), 7.39 – 7.26 (m, 12H), 6.94 – 6.88 (m, 2H), 5.64 (s, 1H), 5.17 (s, 2H), 3.84 –3.81 (m, 1H), 3.78 (s, 3H), 2.95 (t, 2H), 2.77 – 2.71 (m, 2H), 2.60 – 2.48(m, 4H), 1.98 – 1.74 (m, 6H), 1.58 (s, 6H).

[0055] Example 3

[0056] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-methylpropionic acid-(4-chlorophenyl)methyl ester (compound 3), the specific synthetic route of which is shown below:

[0057]

[0058] Following the preparation method in Example 1, replacing benzyl alcohol with p-chlorobenzyl alcohol yields compound 3 with a purity of 95.8%.

[0059] ESI-MS: m / z = 624.3(M+H) + .

[0060] 1 H NMR (400 MHz, CDCl3) δ:7.89 – 7.83 (m, 2H), 7.45 – 7.39 (m, 2H), 7.37 – 7.27 (m, 14H), 5.64 (s, 1H), 5.16 (s, 2H), 3.84 – 3.81 (m, 1H), 2.95(t, 2H), 2.77 – 2.71 (m, 2H), 2.60 – 2.48 (m, 4H), 1.98 – 1.74 (m, 6H), 1.58(s, 6H).

[0061] Example 4

[0062] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-methylpropionic acid-(4-bromophenyl)methyl ester (compound 4), the specific synthetic route of which is shown below:

[0063]

[0064] Following the preparation method in Example 1, replacing benzyl alcohol with p-bromobenzyl alcohol yields compound 4 with a purity of 96.5%.

[0065] ESI-MS: m / z = 668.2(M+H) + .

[0066] 1 H NMR (400 MHz, CDCl3) δ:7.89 – 7.83 (m, 2H), 7.45 – 7.39 (m, 2H), 7.39 – 7.26 (m, 14H), 5.64 (s 1H), 5.16 (s, 2H), 3.84 – 3.81 (m, 1H), 2.95(t, 2H), 2.77 – 2.71 (m, 2H), 2.60 – 2.49 (m, 4H), 1.99 – 1.74 (m, 6H), 1.58(s, 6H).

[0067] Example 5

[0068] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-methylpropionic acid-(4-biphenyl)methyl ester (compound 5), the specific synthetic route of which is shown below:

[0069]

[0070] Compound 5, with a purity of 96.0%, can be prepared by replacing benzyl alcohol with 4-biphenylethanol according to the preparation method in Example 1.

[0071] ESI-MS: m / z = 666.4(M+H) + .

[0072] 1H NMR (400 MHz, CDCl3) δ:7.89 – 7.83 (m, 2H), 7.62 – 7.51 (m, 3H), 7.48 – 7.26 (m, 18H), 5.64 (s, 1H), 5.16 (s, 2H), 3.84 – 3.81 (m, 1H), 2.95(t, 2H), 2.77 – 2.71 (m, 2H), 2.60 – 2.48 (m, 4H), 1.98 – 1.74 (m, 6H), 1.58(s, 6H).

[0073] Comparative Example 1: Commercially available doperazine hydrochloride tablets.

[0074]

[0075] Comparative Example 2:

[0076] Carestin (commercially available product, purchased from Shanghai Yuanye Biotechnology Co., Ltd.)

[0077] .

[0078] Comparative Example 3:

[0079] The comparative compound was prepared according to the preparation method in Example 2 of patent CN1571784A, with a purity of 97.3%.

[0080]

[0081] ESI-MS: m / z = 478.2 (M+H) + .

[0082] 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).

[0083] Experimental Example

[0084] 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.

[0085] 1. Establish a β-amyloid (Aβ)-induced Alzheimer's disease (AD) model.

[0086] (1) Experimental animals: SD rats, acclimatized for one week.

[0087] (2) Aβ 25-35 Preparation of oligomers: Aβ 25-35 Pre-chill hexafluoroisopropanol (HFIP) 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.

[0088] (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.

[0089] 2. Dosing regimen

[0090] Normal rats were used as the blank control group. The AD model rats were randomly divided into the model control group, the treatment groups of Examples 1-5 and the treatment groups of Comparative Examples 1-3, with 8 rats in each group.

[0091] Comparative Example 1 was administered 3 mg / kg of the compound by oral gavage, while the blank control group and the model control group were administered the same volume of physiological saline by gavage. The other groups were given the corresponding compound in equimolar amounts as in Comparative Example 1, once a day for 7 consecutive days.

[0092] 3. Effects of the compound on learning and memory abilities in AD model rats

[0093] 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.

[0094] Table 1: Morris water maze test results for rats in each group (Mean±SD)

[0095]

[0096] Note: Compared with the blank group, P<0.05, P<0.01; compared with the model group, # P<0.05, ## P<0.01; compared with Comparative Example 1, ▲ P<0.05, ▲▲ P<0.01.

[0097] The Morris water maze test results (Table 1) show that, compared with the model group, the compounds in each embodiment of this application (Examples 1-5) significantly shortened the escape latency and increased the number of times the rats crossed the platform (P<0.01), demonstrating a clear improvement in learning and memory function. Particularly noteworthy are the most significant improvements in Examples 1 and 2, where the latency and number of crossings were statistically indistinguishable from the control group, and their numerical performance was close to or even better than the positive control (Comparative Example 1), showing a therapeutic level comparable to clinically effective drugs. In contrast, while the known compound casartine (Comparative Example 2) and its structural analogue (Comparative Example 3) showed some improvement, their latency was significantly longer than the positive control (P<0.01), and the number of crossings was significantly less than the positive control and Examples 1 and 2 of this application (P<0.05), indicating that their cognitive improvement effect was far from ideal. This demonstrates that the compounds in this application can improve the learning and memory abilities of AD model rats.

[0098] 4. Effects of the compound on AChE activity in brain tissue of AD model rats

[0099] 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.

[0100] Table 2: Acetylcholinesterase (AChE) activity in hippocampal tissue of rats in each group (Mean±SD)

[0101]

[0102] Note: Compared with the blank group, P<0.05, P<0.01; compared with the model group, # P<0.05, ## P<0.01; compared with Comparative Example 1, ▲ P<0.05, ▲▲ P<0.01.

[0103] The results of the hippocampal AChE activity assay (Table 2) further confirm the significant advantages of the compounds in this application. The model group showed abnormally elevated AChE activity, while the compounds in the examples of this application, particularly Examples 1, 2, and 5, significantly inhibited the abnormal AChE activity in a dose-dependent or structure-dependent manner (P<0.01), restoring it to levels close to those of the blank and positive control groups. Among them, Example 1 showed the most outstanding inhibitory effect, with its AChE activity value (285.59 μmol / h / g) essentially returning to the normal range, and significantly superior to casartine (365.15 μmol / h / g) and its analogues (381.23 μmol / h / g) (P<0.01), demonstrating its stronger cholinergic system regulatory capacity at the molecular level.

[0104] In summary, the series of novel compounds provided in this application, especially the compounds represented in Examples 1 and 2, have achieved synergistic effects in improving cognitive behavior and correcting key biochemical indicators in AD model animals. They not only significantly outperform carestine, the lead compound, in behavioral aspects, but also achieve effects comparable to clinically positive drugs in regulating key pathological indicators (AChE activity). This comprehensively verifies the remarkable technical efficacy of this class of compounds in combating Alzheimer's disease and provides a solid experimental foundation for developing next-generation multi-target, highly effective therapeutic drugs.

[0105] 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 or a pharmaceutically acceptable salt thereof, characterized in that, The piperidine derivative is selected from the following compounds:

2. The piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, At least one hydrogen atom in the structure of the piperidine derivative is replaced by deuterium.

3. A pharmaceutical composition for 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.

4. The pharmaceutical composition according to claim 3, characterized in that, The composition is formulated for oral, injectable, or nasal administration.

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

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