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

Abstract

This application relates to the field of medicinal chemistry, specifically disclosing a piperidine derivative and its pharmaceutical composition, uses, and preparation method. The piperidine derivative has the following general formula: [Formula omitted]. This piperidine derivative can be effectively used to treat or prevent multiple sclerosis, exhibiting unexpected synergistic effects in animal models: it not only significantly improves neurological function impairment and promotes recovery, but also simultaneously and profoundly reduces the levels of key pro-inflammatory cytokines IFN-γ and IL-17. This invention provides a novel small molecule drug candidate for the treatment of multiple sclerosis that combines central penetration, neuroprotection, and comprehensive immunomodulation.

Description

Technical Field

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

[0002] Multiple sclerosis (MS) is a chronic, immune-mediated disease characterized by inflammatory demyelination of the white matter in the central nervous system and damage to neural axons. Its pathological mechanism involves a complex cascade of immune-inflammatory responses, with Th1 and Th17 cell-mediated immune responses being particularly crucial. This is manifested by abnormally elevated levels of pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-17 (IL-17), which drive inflammatory cell infiltration, myelin destruction, and neuronal damage. Current first-line treatments, such as immunomodulators and monoclonal antibodies, primarily focus on inhibiting peripheral immune activation. While these can reduce clinical relapses, they still have significant limitations in regulating the aforementioned centrally specific inflammatory pathways and effectively penetrating the blood-brain barrier to directly protect neural structures. Therefore, developing small-molecule drugs that can simultaneously act on both the peripheral immune system and central nervous system lesions, possessing both immunomodulatory and direct neuroprotective functions, is a core technological bottleneck that urgently needs to be overcome in the current treatment of MS.

[0003] It is noteworthy that, in extensive research, certain compounds with a piperidine skeleton have been shown to possess anti-inflammatory activity. For example, ebastine and its active metabolite carebastine are known potent and highly selective histamine H1 receptor antagonists, clinically used to treat peripheral allergic diseases such as allergic rhinitis and chronic urticaria. Existing literature clearly states that neither ebastine nor carebastine can cross the blood-brain barrier after oral administration; this characteristic is considered a significant safety advantage as anti-allergy drugs, avoiding the side effects of central nervous system sedation. In other words, existing technology has clearly limited the application of these compounds to peripheral tissues and affirmed and emphasized their inability to cross the blood-brain barrier as a beneficial established property.

[0004] Based on this, the field faces a seemingly contradictory dual dilemma: on the one hand, the treatment of MS urgently requires small molecule drugs that can effectively enter the central nervous system; on the other hand, existing structurally similar active molecules (such as carristin) are generally considered to lack this ability, and their pharmacological mechanisms of action (peripheral antihistamines) are fundamentally different from the core pathological mechanism of MS (central autoimmune inflammation). This leads to a lack of motivation and even technical bias among those skilled in the art when searching for lead compounds for MS treatment, in order to modify or continue using molecular skeletons that are explicitly taught to "not enter the central nervous system and are mainly used for peripheral allergies." Therefore, how to rationally design specific structures to break through the permeability barriers in the existing understanding, successfully shift the activity of compounds from "peripheral antihistamines" to "central immune regulation and neuroprotection," and achieve a fundamental leap in the therapeutic field, has become an unsolved and non-obvious technical problem. Summary of the Invention

[0005] To address the aforementioned technical problems, this application provides a piperidine derivative, its pharmaceutical composition, its uses, and its preparation method.

[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, ester, solvate, or stereoisomer thereof:

[0008]

[0009] (I)

[0010] in,

[0011] n is an integer selected from 1 to 6;

[0012] R1 is selected from hydrogen, alkyl or cycloalkyl groups optionally substituted with one or more of the following substituents: deuterium, alkyl, alkoxy, halogen.

[0013] Furthermore, the above n is selected from integers from 2 to 5.

[0014] Furthermore, R1 is selected from hydrogen or substituted or unsubstituted alkyl groups of C3 to C5.

[0015] Furthermore, the above-mentioned piperidine derivatives are selected from the following compounds:

[0016]

[0017] Furthermore, the hydrogen in the above-mentioned piperidine derivative structure is replaced by one or more deuterium atoms.

[0018] Furthermore, pharmaceutically acceptable salts of the aforementioned compounds 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; preferably hydrochlorides, hydrobroms, methanesulfonates, sulfates, or hydrogen sulfates; more preferably hydrochlorides.

[0019] 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 treatment or prevention of multiple sclerosis.

[0020] Furthermore, the aforementioned drugs are used to improve neurological deficits associated with multiple sclerosis and to reduce the level of at least one of interferon-γ and interleukin-17 in patients with multiple sclerosis.

[0021] Furthermore, the aforementioned multiple sclerosis is selected from relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, or progressive-relapsing multiple sclerosis.

[0022] Thirdly, this application provides a pharmaceutical composition 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.

[0023] Furthermore, the above composition is formulated for oral, parenteral, or nasal administration.

[0024] Fourthly, this application provides a method for preparing the piperidine derivative having the above-mentioned general formula (I), comprising:

[0025] (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 2-acetoxy-2-phenylacetate to give intermediate a, where X is chlorine or bromine and n is an integer selected from 1 to 6;

[0026] (b) The intermediate a is subjected to a nucleophilic substitution reaction with 4-(diphenylmethoxy)piperidine under basic conditions to obtain ester intermediate b;

[0027] (c) Under alkaline conditions, the ester intermediate b is hydrolyzed to convert the terminal methyl ester group into a 2-hydroxyacetic acid group to obtain a piperidine derivative having the general formula (I).

[0028] In summary, this application has the following beneficial effects:

[0029] Existing piperidine compounds with similar structures (such as ebastine and carristin) are explicitly described as being unable to cross the blood-brain barrier, and their applications are strictly limited to the treatment of peripheral allergic diseases. This invention, through specific modifications to the core structure (such as the introduction of a 2-hydroxyacetic acid group), unexpectedly endows these compounds with the ability to penetrate the blood-brain barrier, thereby successfully expanding their activity range from "peripheral antihistamines" to "multiple sclerosis treatment," which requires direct action on the central nervous system. This overcomes the fundamental technical bottleneck that prevents existing analogues from being used for such central nervous system diseases due to their inability to penetrate the brain.

[0030] In an experimental autoimmune encephalomyelitis (EAE) animal model, the compounds of this invention (especially compound 4) significantly improved neurological function scores and promoted weight recovery in the model animals, directly demonstrating their direct neuroprotective or reparative effects. Simultaneously, these compounds efficiently reduced serum levels of key pro-inflammatory cytokines IFN-γ and IL-17, indicating that they simultaneously inhibit the two core inflammatory pathways, Th1 and Th17, in the pathology of multiple sclerosis. This synergistic effect of "neurological function improvement" and "dual anti-inflammatory" overcomes the shortcomings of some existing therapies in terms of neuroprotection and comprehensive immune regulation.

[0031] Compared to the structurally similar but non-penetrating positive control drug Carebastine, the compounds of this invention exhibit superior neurological function improvement and stronger inhibitory activity against factors such as IL-17 in the same EAE model. This demonstrates that the structural modifications of this invention not only overcome permeability limitations but also significantly enhance therapeutic efficacy, achieving unexpected technical results and providing a new small-molecule drug candidate for the treatment of multiple sclerosis. Detailed Implementation

[0032] 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.

[0033] 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:

[0034] "alkyl" refers to a saturated aliphatic hydrocarbon group or linker, preferably a straight-chain or branched group with 1 to 6 carbon atoms.

[0035] "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.

[0036] "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.

[0037] "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.

[0038] "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.

[0039] 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.

[0040] "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 that enhance normal physiological function within its scope.

[0041] "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.

[0042] The structure of the compound in this application was determined by nuclear magnetic resonance (NMR). 1 Determined by ¹H NMR or LC-MS.

[0043] 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.

[0044] The term "room temperature" refers to a temperature between 10 and 35°C.

[0045] 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.

[0046] Example 1

[0047] This embodiment provides a piperidine derivative: 2-[4-(3-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}propionyl)phenyl]-2-hydroxyacetic acid (compound 1), the specific synthetic route of which is shown below:

[0048]

[0049] Step 1: Synthesis of Compound 1a

[0050] 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 6.25 g (0.03 mol) of methyl 2-acetoxy-2-phenylacetate / 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 2.69 g of intermediate 1a, with a yield of 30%.

[0051] Step 2: Synthesis of Compound 1b

[0052] 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. 2.53 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 passed through a silica gel column to give 1.35 g of compound 1b, in 36% yield.

[0053] ESI-MS: m / z = 530.2(M+H) + .

[0054] Step 3: Synthesis of Compound 1

[0055] Compound 1b (530 mg, 1 mmol), 10 ml methanol, and 6 ml 10% NaOH were added to a 25 ml three-necked flask. The mixture was heated to 60 °C and reacted for 2 h. 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, and the mixture was allowed to separate into layers. The layers were washed once with water, and the organic phase was concentrated to dryness. The mixture was then purified by reverse-phase chromatography to obtain 250 mg of compound 1, with a yield of 53% and a purity of 96.2%.

[0056] ESI-MS: m / z = 474.2(M+H) + .

[0057] 1 H NMR (400 MHz, CD3OD): δ 7.89 – 7.83 (m, 2H), 7.54 – 7.49 (m, 2H), 7.39 – 7.26 (m, 10H), 5.64 (s, 1H), 5.14 (s, 1H), 3.84 – 3.81 (m, 1H), 3.07(t, 2H), 2.82 (t, 2H), 2.77 – 2.71 (m, 2H), 2.48 – 2.43 (m, 2H), 1.93 – 1.87(m, 2H), 1.80 – 1.70 (m, 2H).

[0058] Example 2

[0059] This embodiment provides a piperidine derivative: 2-[4-(2-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}acetyl)phenyl]-2-hydroxyacetic acid (compound 2).

[0060]

[0061] Following the preparation method in Example 1, by replacing 3-chloropropionyl chloride in step one with chloroacetyl chloride, compound 2 with a purity of 95.1% can be obtained.

[0062] ESI-MS: m / z = 460.2(M+H) + .

[0063] 1H NMR (400 MHz, CD3OD): δ7.93–7.87 (m, 2H), 7.55–7.49 (m, 2H), 7.39–7.26 (m, 10H), 5.64 (s, 1H), 5.14 (s, 1H), 3.84–3.81 (m, 1H), 3.72 (s, 2H), 2.87–2.82 (m, 2H), 2.57–2.51 (m, 2H), 1.95–1.89 (m, 2H), 1.83–1.77 (m, 2H).

[0064] Example 3

[0065] This embodiment provides a piperidine derivative: 2-[4-(5-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxo-methylenepentyl)phenyl]-2-hydroxyacetic acid (compound 3).

[0066]

[0067] Compound 3 with a purity of 95.6% can be obtained by replacing 3-chloropropionyl chloride with 5-chlorovaleryl chloride in step one according to the preparation method in Example 1.

[0068] ESI-MS: m / z = 502.3(M+H) + .

[0069] 1 H NMR (400 MHz, CD3OD)δ: 7.88 – 7.82 (m, 2H), 7.54 – 7.49 (m, 2H), 7.39 – 7.26 (m, 10H), 5.64 (s, 1H), 5.14 (s, 1H), 3.84 – 3.81 (m, 1H), 2.96(t, 2H), 2.77 – 2.71 (m, 2H), 2.55 – 2.51 (m, 2H), 2.45 (t, 2H), 1.96 – 1.90(m, 2H), 1.82 – 1.75 (m, 2H), 1.67 – 1.53 (m, 4H).

[0070] Example 4

[0071] This embodiment provides a piperidine derivative: 2-[4-(4-{4-[(diphenylmethyl)oxy]hexahydropyridin-1-yl}-1-oxoylidenebutyl)phenyl]-2-hydroxyacetic acid (compound 4).

[0072]

[0073] Compound 4 with a purity of 95.4% can be obtained by replacing 3-chloropropionyl chloride in step one with 4-chlorobutyryl chloride according to the preparation method in Example 1.

[0074] ESI-MS: m / z = 488.2(M+H) + .

[0075] 1 H NMR (400 MHz, CD3OD)δ: 7.88 – 7.82 (m, 2H), 7.54 – 7.49 (m, 2H), 7.39 – 7.28 (m, 10H), 5.64 (s, 1H), 5.14 (s, 1H), 3.84 – 3.81 (m, 1H), 2.94(t, 2H), 2.77 – 2.71 (m, 2H), 2.57 – 2.48 (m, 4H), 1.98 – 1.74 (m, 6H).

[0076] Experimental Example

[0077] Effects of the compound on neurological function in a mouse model of multiple sclerosis

[0078] This experimental example aims to evaluate the effects of the compounds in this application series on improving neurological dysfunction and inflammatory factor levels in experimental autoimmune encephalomyelitis (EAE) model mice.

[0079] 1. Establish an experimental autoimmune encephalomyelitis (EAE) model.

[0080] (1) Experimental animals: 64 female C57BL / 6 mice, aged 4-5 weeks, were randomly divided into normal control group, model control group, positive control group (methylprednisolone sodium succinate injection), carebastine group and compound 1-4 group, with 8 mice in each group.

[0081] (2) Model establishment: Except for the normal control group, the other mice were subcutaneously injected with 100 µL of Freund's complete adjuvant (containing 400 µg of Mycobacterium tuberculosis H37RA and 300 µg of myelin oligodendrocyte glycoprotein peptide MOG35-55) at three different sites on their backs; at the same time, 400 ng of pertussis toxin (PTX) was injected intraperitoneally. After an interval of 48 h, 200 ng of pertussis toxin (PTX) was injected intraperitoneally again to induce the establishment of the EAE mouse model. Mice in the normal control group were subcutaneously injected with Freund's adjuvant without MOG35-55.

[0082] 2. Dosing regimen

[0083] One day before modeling, the carbastine group was given 3 mg / kg of carebastine orally by gavage, and the compounds 1-4 groups were given the same amount of carebastine as the carbastine group, and the administration was continued for two weeks. On the 8th day after modeling, the positive control group was given 20 mg / kg of methylprednisolone sodium succinate injection intraperitoneally, and the administration was continued for 3 days.

[0084] 3. Effects of the compound on neurological function in EAE model mice

[0085] On day 21 after modeling, the weight and neurological function scores of mice in each group were recorded. The neurological function scoring criteria are shown in Table 1:

[0086] Table 1. Neurological Function Scoring Criteria

[0087]

[0088] The neurological function scores and weight records of the mice in each group are shown in Table 2:

[0089] Table 2. Neurological function scores and body weight of mice on day 21 of modeling (Mean±SD)

[0090]

[0091] As can be seen from Table 2:

[0092] This experiment successfully constructed an EAE model simulating MS pathology. The control group mice exhibited significant neurological dysfunction (score 1.75) and weight loss (15.00 g), a stark contrast to the normal control group, validating the reliability of the disease model. From compound 1 to compound 4, with structural changes, neurological function improvement and weight recovery showed a trend of optimization, with compound 4 showing the most comprehensive and prominent effects. Other compounds also demonstrated clear therapeutic effects in terms of neurological function scores and weight recovery, indicating that the compounds in this application can effectively alleviate neurological dysfunction and improve overall health in EAE model mice.

[0093] Compared to the prior art compound Carebastine, compounds 1-4 of this invention exhibit fundamental advantages. Specifically, the Carebastine group showed extremely limited improvement in neurological function score (1.49) and weight recovery (15.63 g), significantly weaker than all compounds of this invention (groups 1-4). This result directly confirms that prior art Carebastine, due to its inability to effectively penetrate the blood-brain barrier, is difficult to substantially intervene in central nervous system damage. However, the compounds of this invention, through specific structural modifications, successfully overcome this permeability barrier, thereby achieving a qualitative leap from "almost ineffective" to "significantly effective" in central nervous system protection.

[0094] Compared to conventional positive control drugs, the preferred compound of this invention (compound 4) demonstrates a significant improvement in overall efficacy: the positive control group (score 1.00, weight 17.38 g) represents the expected level of existing treatments. However, compound 4 of this invention further significantly reduced the neurological function score to 0.65, while simultaneously increasing weight recovery to 18.63 g, with statistically significantly better results than the positive control group. This proves that this invention not only solves the problem of carebastine compounds' inability to effectively penetrate the blood-brain barrier, but its preferred compound even surpasses existing treatment benchmarks in efficacy, achieving unexpected technological advancements.

[0095] 4. Effects of the compound on the levels of inflammatory factors in EAE model mice

[0096] After the neurological function assessment, blood samples were collected from each group of mice via the tail vein. After standing for 1 hour, the serum was separated by centrifugation. The levels of interferon-γ (IFN-γ) and interleukin-17 (IL-17) in the serum were detected by enzyme-linked immunosorbent assay (ELISA). The results of each group are shown in Table 3.

[0097] Table 3. Regulation of IFN-γ and IL-17 by the compounds in each group of mice (Mean±SD)

[0098]

[0099] As shown in Table 3, serum IFN-γ and IL-17 levels in the model control group mice were significantly elevated, indicating that the EAE model is accompanied by significant inflammation and immune abnormalities. All drug-treated groups were able to reduce the levels of these inflammatory factors to varying degrees. Specifically:

[0100] The existing compound Carebastine exhibits limited and incomplete peripheral anti-inflammatory activity: while the Carebastine group reduced IFN-γ (22.11 pg / mL) and IL-17 (206.01 pg / mL) to some extent, their levels were still much higher than those of the normal control, and the inhibition of IL-17 was particularly insufficient. This is consistent with its known histamine H1 receptor antagonists, which mainly act on the periphery, and its anti-inflammatory spectrum and potency fail to cover the core central immunopathology of MS.

[0101] The compounds of this invention exhibit immunomodulatory capabilities far exceeding those of Carebastine, with compound 4 showing the most significant effect. It reduced IFN-γ and IL-17 levels to 14.38 pg / mL and 186.45 pg / mL, respectively, which are very close to the normal control group and statistically significantly superior to the positive control and Carebastine group. This demonstrates that the compounds of this invention can not only effectively enter the central nervous system but also strongly and evenly inhibit the two independent inflammatory pathways crucial in the progression of MS: Th1 (IFN-γ driven) and Th17 (IL-17 driven).

[0102] In summary, this invention addresses the technical bottleneck of existing piperidine compounds' inability to penetrate the blood-brain barrier and thus their inability to be used in the treatment of central nervous system diseases. By introducing specific structural modifications such as a 2-hydroxyacetic acid group, this permeability limitation has been successfully overcome. Experiments show that the obtained compound not only effectively enters the central nervous system but also unexpectedly achieves both excellent neuroprotection (significantly improving neurological function scores and body weight in the EAE model) and comprehensive immunomodulation (deeply and synergistically inhibiting IFN-γ and IL-17). This qualitative leap from "peripherally limited" to "centrally synergistic therapy" solves the key challenges of drug penetration and intervention in multiple pathological processes in the treatment of multiple sclerosis, achieving outstanding results that were unpredictable with existing technologies.

[0103] 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） in, n is an integer selected from 1 to 6; R1 is hydrogen.

2. The piperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The piperidine derivative is selected from the following compounds:

3. The piperidine derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The hydrogen in the piperidine derivative structure is replaced by one or more deuterium atoms.

4. Use of a piperidine derivative as described in any one of claims 1-3, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of multiple sclerosis.

5. The use according to claim 4, characterized in that, The drug is used to improve neurological deficits associated with multiple sclerosis and to reduce the level of at least one of interferon-γ and interleukin-17 in patients with multiple sclerosis.

6. A pharmaceutical composition comprising a therapeutically effective amount of a piperidine derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, characterized in that, The composition is formulated for oral and parenteral administration.

8. A method for preparing a piperidine derivative having general formula (I) as described in claim 1, 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 2-acetoxy-2-phenylacetate to give intermediate a, where X is chlorine or bromine and n is an integer selected from 1 to 6; (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 2-hydroxyacetic acid group to obtain a piperidine derivative having the general formula (I).

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