N-propyl-4-phenylindole derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an N-propyl-4-phenylindole derivative as well as a preparation method and application thereof. The structure of the N-propyl-4-phenylindole derivative is as shown in the specification. The compound takes an indole ring as a parent nucleus, a phenyl substituent is introduced to the fourth site of the parent nucleus, a flexible n-propyl connecting chain is connected to the first site of the parent nucleus, the hydrophobic interaction with a receptor is enhanced through 4-phenyl, the overall physicochemical properties of molecules are adjusted, diversified alkaline amino fragments are flexibly connected through an N-propyl chain, and the compound is obtained. And the N-propyl-4-phenylindole derivative is obtained. Through the unique structure, strong H3 receptor antagonistic activity and anticonvulsion effect are achieved, and meanwhile, the compound has good safety and central nervous system penetrability and is expected to be developed into a new generation of high-efficiency and low-toxicity antiepileptic drug.

Description

Technical Field

[0001] This invention belongs to the field of antiepileptic drug technology, specifically relating to an N-propyl-4-phenylindole derivative, its preparation method, and its application. Background Technology

[0002] Epilepsy is a chronic neurological disorder caused by abnormal synchronous discharges of neurons in the brain. Clinically, it mainly manifests as recurrent, transient disturbances of motor, sensory, or consciousness. Currently, commonly used antiepileptic drugs exert their effects by regulating ion channels or neurotransmitter receptors; however, drug resistance exists, and long-term use can easily lead to adverse reactions such as cognitive decline and liver and kidney damage. To improve treatment efficacy and eliminate or reduce side effects, compounds with novel structural features and mechanisms of action are needed.

[0003] Histaminergic neural systems play a crucial role in epilepsy regulation. Histamine, an inhibitory neurotransmitter in the brain, can regulate the release of itself and other neurotransmitters (such as glutamate, γ-aminobutyric acid, acetylcholine, and dopamine) through negative feedback from presynaptic H3 receptors. Antagonizing H3 receptors can increase the concentration of inhibitory neurotransmitters in the synaptic cleft, thereby helping to suppress neuronal overexcitation. Therefore, developing highly selective histamine H3 receptor antagonists has become a novel strategy in antiepileptic drug development.

[0004] In the field of antiepileptic drugs, several H3 receptor antagonists have been reported to possess anticonvulsant activity. For example, Reference 1: https: / / doi.org / 10.3389 / fphar.2024.1364353. The compound DL76 reported in Reference 1 exhibited a dose-dependent protective effect in a maximal electroshock (MES) model, significantly shortening the hindlimb tetany time in electrically stimulated mice at 60 mg / kg; other non-imidazolium derivatives such as E159 and E169 have also shown anticonvulsant effects in animal epilepsy models.

[0005] Despite the aforementioned research progress, H3 receptor antagonists currently in clinical trials or preclinical development still have some shortcomings. Most compounds suffer from insufficient H3R selectivity, poor blood-brain barrier penetration, and low in vivo activity, hindering their clinical development. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a novel N-propyl-4-phenylindole derivative with a novel mechanism of action and showing potential for the development of antiepileptic drugs, along with its preparation method and applications. This type of derivative participates in the regulation of neural signals in epileptic seizures by acting on histamine H3 receptors and negatively regulating the release of histamine and other neurotransmitters.

[0007] This invention uses an indole ring as the parent nucleus, introducing a phenyl substituent at position 4 and a flexible n-propyl linker at position 1. The introduction of the phenyl group increases the overall rigidity and hydrophobicity of the molecule, optimizing its binding ability to the transmembrane hydrophobic region of the H3 receptor, thereby improving receptor affinity and antagonistic activity. It also modulates the lipophilicity of the entire molecule to improve its ability to penetrate the blood-brain barrier. Simultaneously, different amine groups are introduced onto the n-propyl linker. Utilizing the appropriate length and flexibility of the propyl chain, the terminal basic amine group can precisely bind to the receptor, forming effective ionic or hydrogen bonds with key amino acid residues. Furthermore, by varying the structure of the R2 group (including cyclic amines, open-chain amines, and different substitution modes), the influence of the basic center on H3 receptor antagonistic activity, subtype selectivity, and brain penetration is studied, aiming to optimize molecules with both potent antagonistic activity and excellent pharmacokinetic properties.

[0008] This invention provides an N-propyl-4-phenylindole derivative, the chemical structural formula of which is as follows: ; In the formula, R1 is H or a halogen; R2 is selected from any of the following groups: .

[0009] Preferably, the N-propyl-4-phenylindole derivative is selected from one of the following compounds: .

[0010] Preferably, the N-propyl-4-phenylindole derivative is an addition salt of the compound represented by the general structural formula and a pharmaceutically acceptable acid; the pharmaceutically acceptable acid is any one of hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, methanesulfonic acid, and maleic acid.

[0011] This invention provides a method for preparing an N-propyl-4-phenylindole derivative, comprising the following steps: The 4-bromo-1H-indole was subjected to a Suzuki coupling reaction with a phenylboronic acid compound to give intermediate 2; intermediate 2 was then subjected to an N-alkylation reaction with a chloropropylamine reagent to give an N-propyl-4-phenylindole derivative; the synthetic route is as follows: .

[0012] Preferably, the phenylboronic acid compounds are phenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, or 4-chlorophenylboronic acid; the chloropropylamine reagents are N-(3-chloropropyl)piperidine hydrochloride, 4-(3-chloropropyl)morpholine, 3-chloro-N,N-diethylpropyl-1-amine, N-(3-chloropropyl)dibutylamine, or 1-(3-chloropropyl)-4-phenylpiperidine.

[0013] Preferably, the specific preparation method of intermediate 2 is as follows: 4-Bromo-1H-indole, a phenylboronic acid compound, a base, and a palladium catalyst were dissolved in a solvent, and a Suzuki coupling reaction was carried out to give intermediate 2.

[0014] Preferably, the molar ratio of 4-bromo-1H-indole, phenylboronic acid compound to base is 1:1.1-1.3:2-4; and the molar ratio of 4-bromo-1H-indole to palladium catalyst is 1:0.05.

[0015] Preferably, the molar ratio of intermediate 2 to chloropropylamine reagent is 1:1 to 1.2.

[0016] Preferably, the temperature for the Suzuki coupling reaction is 60°C to 70°C; and the temperature for the N-alkylation reaction is 80°C to 90°C.

[0017] Preferably, the solvent is 1,4-dioxane and water, with a volume ratio of 1,4-dioxane to water of 3:1.

[0018] Preferably, the alkali is potassium carbonate.

[0019] Preferably, the palladium catalyst is PdCl2(PPh3)2.

[0020] This invention provides the application of an N-propyl-4-phenylindole derivative in the preparation of drugs for treating epilepsy.

[0021] Compared with the prior art, the present invention has the following technical effects: 1. This invention provides an N-propyl-4-phenylindole derivative with antiepileptic activity. This type of compound uses an indole ring as the parent nucleus, introduces a phenyl substituent at the 4-position of the parent nucleus, and connects a flexible n-propyl linker chain at the 1-position. The 4-phenyl group enhances the hydrophobic interaction with the receptor and adjusts the overall physicochemical properties of the molecule. Then, the N-propyl chain flexibly connects various basic amine fragments to obtain an N-propyl-4-phenylindole derivative with potent H3 receptor antagonistic activity, excellent anticonvulsant effect, good central nervous system penetration and safety.

[0022] 2. The N-propyl-4-phenylindole derivative of the present invention exhibits potent anticonvulsant activity; wherein, the half-maximal effective dose (ED50) of compound 3n is... 50 At a dose as low as 16.44 mg / kg, it effectively counteracts tonic-clonic seizures in the hind limbs of mice. Mechanism of action studies have shown that the anticonvulsant activity of compound 3n is closely related to its antagonistic effect on histamine H3 receptors; this effect can be reversed by the H3 receptor agonist RAMH, confirming that its antiepileptic effect is achieved through the regulation of the histaminergic nervous system.

[0023] 3. The N-propyl-4-phenylindole derivative of this invention can inhibit 98.66% of convulsive-like movements in a PTZ-induced zebrafish convulsion model at a concentration of 10 µM. Its activity is significantly better than that of carbamazepine, indicating that it has better activity potential and application advantages as an H3R-targeted anti-epileptic candidate compound.

[0024] 4. The N-propyl-4-phenylindole derivative of the present invention exhibits excellent blood-brain barrier permeability. After intravenous administration for 90 minutes, the drug concentration ratio in the rat brain and serum reached 1.16.

[0025] 5. The N-propyl-4-phenylindole derivative provided by this invention achieves potent H3 receptor antagonistic activity and anticonvulsant effect through its unique structure, while also possessing good safety and central nervous system penetration, and is expected to be developed into a new generation of highly effective and low-toxicity antiepileptic drugs. Attached Figure Description

[0026] Figure 1 This is the chemical structural formula of the N-propyl-4-phenylindole derivative of the present invention.

[0027] Figure 2 This is a comparison chart of the effects of the test compound and the positive control drug at different time points in the MES model test.

[0028] Figure 3 This is a graph showing the inhibitory effects of the tested compounds 3m and 3n on PTZ-induced convulsive movements in zebrafish. Specifically, A shows the results of measuring the effects of different concentrations of carbamazepine on the PTZ-induced behavioral trajectories of zebrafish; B shows the results of measuring the effects of different concentrations of compound 3m on the PTZ-induced behavioral trajectories of zebrafish; and C shows the results of measuring the effects of different concentrations of compound 3n on the PTZ-induced behavioral trajectories of zebrafish.

[0029] Figure 4 The graphs show the effects of different concentrations of compounds 3m and 3n on the survival rate of SH-SY5Y and PC12 cells. Specifically, A shows the effects of different concentrations of compounds 3m and 3n on the survival rate of SH-SY5Y cells; B shows the effects of different concentrations of compounds 3m and 3n on the survival rate of PC12 cells.

[0030] Figure 5 This is a plasma drug concentration-time curve of compound 3n after intravenous injection and oral administration in rats.

[0031] Figure 6 This is a graph showing the drug concentration distribution in rat brain tissue and plasma at different time points after intravenous injection of compound 3n, as well as the brain-blood concentration ratio. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0033] Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] The technical solution of the present invention will be further described below through specific embodiments.

[0035] In the following embodiments, unless otherwise specified, the methods described are conventional methods; and unless otherwise specified, the reagents and materials described are commercially available.

[0036] Example 1 A method for preparing an N-propyl-4-phenylindole derivative includes the following steps: Step 1: Preparation of intermediates: 4-bromo-1 H Indole (0.5 mmol), K₂CO₃ (1.5 mmol), and phenylboronic acid (0.6 mmol) were added to 12 mL of an aqueous solution of 1,4-dioxane (1,4-dioxane to H₂O volume ratio 3:1), degassed under N₂ for 15 min, then treated with PdCl₂(PPh₃)₂ (0.025 mmol) and reacted overnight at 65 °C under N₂ protection. The extent of reaction was determined by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, concentrated, diluted with NaOH (2 mol / L, 10 mL), and extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed once with saturated brine (10 mL), dried overnight with anhydrous magnesium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a white solid, which was intermediate 2a.

[0037] Step 2: Preparation of N-propyl-4-phenylindole derivatives: Intermediate 2a (0.5 mmol), NaH (1.5 mmol), and acetonitrile (15 mL) were added to a reaction flask and reacted at room temperature for 30 min. Then, N-(3-chloropropyl)piperidine hydrochloride (1 mmol) was added, and the mixture was stirred overnight in an oil bath at 80°C. The extent of the reaction was detected by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain a yellow oily substance, which was compound 3a, with a yield of 67%.

[0038] Example 2 The method for preparing an N-propyl-4-phenylindole derivative is basically the same as that in Example 1, except that the phenylboronic acid reagent in step 1 and the chloropropylamine reagent in step 2 are different, as shown in Table 1; the specific synthetic route is as follows: .

[0039] Table 1. Reactant composition of the N-propyl-4-phenylindole derivative of the present invention. The NMR data of the intermediates prepared in Examples 1 and 2 and the N-propyl-4-phenylindole derivatives are as follows: NMR data for compound 2a: 1 H-NMR (CDCl3, 400 MHz): δ 6.65 (t, J = 2.7 Hz, 1H, Indole-H), 7.11-7.64 (m, 9H, Ph-H, Indole-H), 8.10 (s, 1H, NH). 13 C NMR (CDCl3, 101 MHz) δ 141.29, 136.26, 134.51, 128.81, 128.51, 126.96, 126.16, 124.47,122.35, 119.79, 110.25, 102.20. ESI-HRMS calculated for C 14 H 12 N + ([M + H)) + ):194.0964; measured: 194.0965. NMR data for compound 2b: 1 H-NMR (CDCl3, 500 MHz): δ 6.26 (t, J = 4.1 Hz, 1H, Indole-H), 7.04-7.45 (m, 8H, Ph-H, Indole-H) 8.12 (s, 1H, NH). 13 C NMR (CDCl3, 126 MHz) δ138.67, 134.70, 132.18, 130.90, 130.84, 128.77, 127.37, 125.99,125.45, 123.32, 120.67, 119.94, 109.68, 101.39. forC 14 H 11 ClN + ([M + H)) + ): 228.0575; measured: 228.0582. NMR data for compound 2c: 1 H-NMR (CDCl3, 400 MHz): δ 6.70 (t, J = 2.1 Hz, 1H, Indole-H), 7.16-7.41 (m, 6H, Ph-H, Indole-H), 7.58 (dt, 1H, J = 7.6, 1.4 Hz, Ph-H),7.69 (t, 1H, J = 1.8 Hz, Ph-H) 8.26 (s, 1H, NH). 13 C NMR (CDCl3, 101 MHz) δ 143.07, 136.19, 134.28, 132.91, 129.71, 128.73, 126.93, 126.89, 125.93,124.74, 122.30, 119.79, 110.76, 101.83. for C 14 H 11 ClN + ([M +H)) + ): 228.0575; measured: 228.0574. NMR data of compound 2d: 1 H-NMR (CDCl3, 400 MHz): δ 6.67 (t, J= 2.2 Hz, 1H, Indole-H), 7.16 (dd, J = 7.3, 0.8 Hz, 1H, Indole-H), 7.24 - 7.29 (m, 2H, Ph-H), 7.39 (d, J = 8.1 Hz, 1H, Ph-H), 7.42 - 7.46 (m, 2H, Ph-H), 7.65 - 7.61 (m, 2H, Ph-H), 8.25 (s, 1H, NH). 13 C NMR (CDCl3, 101 MHz) δ 139.67, 136.19, 133.13, 132.79, 129.96, 128.63, 125.93, 124.66, 122.32, 119.66, 110.53, 101.85. ESI-HRMS calculated for C 14 H 11 ClN + ([M + H] + ): 228.0575; measured: 228.0586. 1H-NMR data of compound 3a: 1 1H-NMR (CDCl3, 400 MHz): δ 0.86 - 0.98 (m, 2H, CH2), 1.26 - 1.42 (m, 8H, NCH2CH2, NCH2), 1.99 - 2.05 (m, 2H, NCH2CH2), 2.31 (t, J J = 6.3 Hz, 2H, NCH2), 4.23 (t, J J = 6.7 Hz, 2H, NCH2), 6.26 (s, 1H, Indole-H), 7.09 - 7.52 (m, 9H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ 139.65, 135.95, 133.14, 131.87, 129.77, 128.33, 127.19, 126.42, 121.03, 120.43, 109.05, 100.76, 66.99, 55.36, 53.57, 43.95, 26.89. ESI-HRMS calculated for C 22 H 27 N2 + ([M + H]+ ): 319.2169; measured: 319.2181. NMR data for compound 3b: 1 H-NMR (CDCl3, 500 MHz): δ 1.18-1.22 (m, 2H, CH2),1.34-1.38(m, 4H, NCH2CH2), 1.52-1.56 (m, 4H, NCH2), 1.97-2.03 (m, 2H, NCH2CH2),2.17 (t, J = 7.0 Hz, 2H, NCH2), 4.15 (t, J = 6.8 Hz, 2H, NCH2), 6.54 (d, J = 3.5 Hz, 1H, Indole-H), 7.01-7.25 (m, 6H, Ph-H, Indole-H), 7.39 (dd, 1H, J = 4.8, 1.9 Hz,Ph-H),7.44 (dd, 1H, J = 5.5, 1.5 Hz, Ph-H). 13 C NMR (CDCl3, 126 MHz) δ 138.72,134.99, 132.17, 130.89, 128.76, 127.29, 127.16, 125.39, 121.18, 121.12,120.02, 119.42, 108.08, 99.74, 54.81, 53.42, 43.28, 26.20, 24.72, 23.26. ESI-HRMS calculated for C 22 H 26 ClN2 + ([M + H)) + ): 353.1779; measured: 353.1786. NMR data of compound 3c: 1 H-NMR (CDCl3, 500 MHz): δ 0.81-0.77 (m, 2H, CH2),1.37-1.31(m, 4H, NCH2CH2), 1.56 (t, J = 5.6 Hz, 4H, NCH2), 2.02-1.96 (m, 2H, NCH2CH2), 2.24 (t,J = 7.1 Hz, 2H, NCH2), 4.16 (t, J = 6.8 Hz, 2H, NCH2), 6.54 (d, J = 6.8 Hz, 1H, Indole-H), 7.06 - 7.32 (m, 6H, Ph-H, Indole-H), 7.58 (dt, 1H, J = 7.6, 1.2 Hz, Ph-H) 7.61 (t, 1H, J = 1.5 Hz, Ph-H). 13 C NMR (CDCl3, 126 MHz) δ 142.16, 135.43, 133.24, 132.01, 128.64, 127.76, 127.59, 125.91, 125.84, 125.58, 120.69, 118.28, 108.16, 99.24, 54.68, 53.40, 43.24, 26.10, 24.66, 23.21. ESI-HRMS calculated for C 22 H 26 ClN2 + ([M + H] + ): 353.1779; measured: 353.1794. 1H-NMR data of compound 3d: 1 1H-NMR (CDCl3, 500 MHz): 1 1H-NMR (CDCl3, 500 MHz): δ 0.78 - 0.81 (m, 2H, CH2), 1.35 - 1.38 (m, 4H, NCH2CH2), 1.72 (d, J = 14.3 Hz, 4H, NCH2), 2.17 - 2.25 (m, 2H, NCH2CH2), 2.40 (d, J = 10.7, Hz, 2H, NCH2), 4.32 (t, J = 6.2 Hz, 2H, NCH2), 6.57 (d, J = 2.9 Hz, 1H, Indole-H), 7.08 - 7.38 (m, 6H, Ph-H, Indole-H), 7.53 (t, 1H, J= 2.2 Hz, Ph-H)7.54 (t, 1H, J = 2.2 Hz, Ph-H). 13 C NMR (CDCl3, 126 MHz) δ 142.16, 135.43, 133.24, 132.01, 128.64, 127.76, 127.59,125.91, 125.84, 125.58, 120.69, 118.28, 108.16, 99.24, 54.68, 53.40, 43.24,26.10, 24.66, 23.21. ESI-HRMS calculated for C 22 H 26 ClN2 + ([M + H)) + ): 353.1779; measured: 353.1794. NMR data for compound 3e: 1 H-NMR (CDCl3, 400 MHz): δ 2.01-2.04 (m, 2H,NCH2CH2), 2.29-2.32 (m, 2H, NCH2), 2.40 (s, 4H, NCH2), 3.73 (t, J = 4.6 Hz, 4H,OCH2), 4.25 (t, J = 6.7 Hz, 2H, NCH2), 6.65 (t, J = 3.8 Hz, 1H, Indole-H), 7.15-7.70 (m, 8H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ 141.29, 136.45, 134.64,128.81, 128.44, 128.30, 126.87, 126.77, 121.74, 119.28, 108.57, 100.62,67.02, 55.35, 53.61, 43.98, 26.91. ESI-HRMS calculated for C 21 H 25 N2O + ([M + H)) + ): 321.1961; measured: 321.1974. NMR data for compound 3f: 1 H-NMR (CDCl3, 500 MHz): δ 1.94-1.98(m, 2H, NCH2CH2),2.24 (t, J = 6.8 Hz, 2H, NCH2), 2.34 (s, 4H, NCH2), 3.65 (t, J = 4.7 Hz, 4H,OCH2), 4.16 (t, J = 6.7 Hz, 2H, 6.18 (d, 1H, J = 2.6 Hz, Indole-H), 7.03-7.44 (m,8H, Ph-H, Indole-H). 13 C NMR (CDCl3, 126 MHz) δ 138.67, 134.98, 132.16, 130.86,128.76, 127.32, 127.15, 125.40, 121.21, 121.16, 120.04, 119.44, 108.03,99.79, 65.93, 54.37, 52.55, 42.95, 25.87. ESI-HRMS calculated for C 21 H 24 ClN2O + ([M + H)) + ): 355.1572; measured: 355.1584. NMR data for 3g of compound: 1 H-NMR (CDCl3, 400 MHz): δ 2.00-2.04 (m, 2H,NCH2CH2), 2.29 (t, J = 6.8 Hz, 2H, NCH2), 2.41 (s, 4H, NCH2), 3.74 (t, J = 4.6 Hz, 4H, OCH2), 4.25 (t, J = 6.7 Hz, 2H, 6.63 (d, J = 3.2 Hz, 1H, Indole-H),7.69-7.15(m, 8H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ143.11, 136.43, 134.25,133.05, 129.68, 128.76, 128.62, 126.92, 126.89, 126.57, 121.71, 119.31,109.14, 100.28, 66.98, 55.25, 53.57, 43.95, 26.86. ESI-HRMS calculated forC 21 H 24 ClN2O + ([M + H)) + ): 355.1572; measured: 355.1585. NMR data of compound 3h: 1 H-NMR (CDCl3, 400 MHz): δ 1.99-2.06 (m, 2H,NCH2CH2), 2.30 (t, J = 6.8 Hz, NCH2), 2H,2.42 (s, 4H, NCH2), 3.73 (t, J = 4.6 Hz, 4H, OCH2), 4.25 (t, J = 6.7 Hz, 2H, 6.60 (d, J = 3.1 Hz, 1H, Indole-H), 7.13-7.45(m, 6H, Ph-H, Indole-H), 7.63 (d, J = 8.4 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 139.69, 136.40, 133.26, 132.74, 129.99, 128.60, 128.54, 126.55, 121.74,119.19, 108.90, 100.29, 66.94, 55.26, 53.54, 43.94, 26.83. ESI-HRMScalculated for C 21 H 24 ClN2O + ([M + H)) + ): 355.1572; measured: 355.1585. NMR data for compound 3i: 1 H-NMR (CDCl3, 400 MHz): δ1.79 - 1.84 (m, 4H, NCH2CH2), 1.99 - 2.08 (m, 4H, NCH2), 2.35 (t, J J = 6.9 Hz, 2H, NCH2CH2), 2.45 - 2.51 (m, 1H, CH), 3.01 (d, J J = 11.0 Hz 2H, NCH2), 4.25 (t, J J = 6.6 Hz, 2H, NCH2), 6.66 (d, 1H, J J = 2.8 Hz, Indole - H), 7.17 - 7.48 (m, 9H, Ph - H, Indole - H), 7.71 (d, 2H, J J = 7.9 Hz, Ph - H). 13 C NMR (CDCl3, 101 MHz) δ 146.29, 141.29, 136.41, 134.53, 128.79, 128.41, 128.33, 126.84, 126.71, 126.14, 121.68, 119.22, 108.72, 108.62, 101.39, 100.49, 55.42, 54.29, 44.25, 42.66, 33.47, 27.51. ESI - HRMS calculated for C 28 H 21 N2 + ([M + H] + ): 395.2482; measured: 395.2497. 1H - NMR data of compound 3j: 1 1H - NMR (CDCl3, 400 MHz): δ 1.84 - 1.86 (m, 4H, NCH2CH2), 2.02 - 2.14 (m, 4H, NCH2), 2.38 (t, J J = 6.7 Hz, 2H, NCH2CH2), 2.46 - 2.52 (m, 1H, CH), 3.03 (d, J J = 10.4 Hz 2H, NCH2), 4.25 (t, J J = 6.7 Hz, 2H, NCH2), 6.27 (d, 1H, J= 2.9 Hz, Indole-H), 7.06-7.53 (m, 13H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ 146.26, 139.70, 135.98, 133.17, 131.97, 131.90, 129.77,128.42, 128.32, 128.21, 127.59, 126.84, 126.42, 126.16, 121.02, 120.42,109.11, 100.72, 55.49, 54.30, 44.29, 42.65, 33.45, 27.53. ESI-HRMS calculated for C 28 H 20 ClN2 + ([M + H)) + ): 429.2092; measured: 429.2104. NMR data for compound 3k: 1 H-NMR (CDCl3, 500 MHz): δ 1.80-1.85 (m, 4H, NCH2CH2), 2.01-2.08 (m, 4H, NCH2), 2.35 (t, J = 7.0 Hz, 2H, NCH2CH2), 2.46-2.52(m, 1H, CH), 3.01 (d, J = 11.3 Hz 2H, NCH2), 4.26 (t, J = 6.8 Hz, 2H, NCH2), 6.63(d, 1H, J = 3.1 Hz, Indole-H), 7.03-7.40 (m, 11H, Ph-H, Indole-H), 7.58 (d, 1H, J = 7.6 Hz, Ph-H), 7.69 (d, J = 1.6 Hz, 1H, Ph-H). 13 C NMR (CDCl3, 126 MHz) δ146.29, 143.23, 136.52, 134.30, 133.06, 129.70, 128.82, 128.68, 128.47,126.98, 126.90, 126.88, 126.64, 126.21, 121.73, 119.33, 109.24, 100.27,55.41, 54.34, 44.31, 42.69, 33.49, 27.53. ESI-HRMS calculated for C 28 H 20 ClN2 + ([M + H)) + ): 429.2092; measured: 429.2105. NMR data for compound 3l: 1 H-NMR (CDCl3, 500 MHz): δ 1.78-1.86 (m, 4H,NCH2CH2), 2.01-2.08(m, 4H, NCH2), 2.35 (t, J = 7.0 Hz, 2H, NCH2CH2), 2.46-2.52(m, 1H, CH), 3.01 (d, J = 11.4 Hz 2H, NCH2), 4.26 (t, J = 6.8 Hz, 2H, NCH2), 6.60(d, 1H, J = 3.1 Hz, Indole-H), 7.13-7.44 (m, 11H, Ph-H, Indole-H), 7.63 (d, J =8.5 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 146.29, 139.82, 136.51, 133.28,132.77, 130.05, 128.63, 128.60, 128.46, 126.87, 126.64, 126.21, 121.75,119.21, 109.02, 100.28, 55.41, 54.34, 44.31, 42.69, 33.49, 27.53. ESI-HRMScalculated for C 28 H 20 ClN2 + ([M + H))+ ): 429.2092; measured: 429.2089. NMR data for compound 3m: 1 H-NMR (CDCl3, 400 MHz): δ 1.01 (t, J = 7.1 Hz, 6H,CH3), 1.98-2.05 (m, 2H, NCH2CH2), 2.46 (t, J = 7.1 Hz, 2H, NCH2), 2.53 (q, J = 7.1Hz, 4H, NCH2CH3), 4.21 (t, J = 7.1 Hz, 2H, NCH2), 6.65 (d, 1H, J = 3.1 Hz, Indole-H), 7.16-7.45 (m, 9H, Ph-H, Indole-H), 7.71 (d, J = 7.1 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 141.32, 136.35, 134.56, 128.80, 128.41, 128.27, 126.83,126.76, 121.67, 119.21, 108.59, 100.44, 49.94, 46.64, 44.48, 31.64, 11.50.ESI-HRMS calculated for C 21 H 27 N2 + ([M + H)) + ): 307.2169; measured: 307.2182. NMR data for compound 3n: 1 H-NMR (CDCl3, 400 MHz): δ 1.00 (t, J = 7.1 Hz, 6H,CH3), 1.98-2.05 (m, 2H, NCH2CH2), 2.46 (t, J = 6.9 Hz, 2H, NCH2), 2.53 (q, J =7.1, Hz 4H, NCH2CH3), 4.21 (t, J= 7.1 Hz, 2H, NCH2), 6.26 (d, J = 2.8 Hz, 1H, Indole-H), 7.09-7.53 (m, 11H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ 139.72,135.91, 133.17, 131.91, 131.89, 129.76, 128.31, 128.16, 127.62, 126.42,120.99, 120.38, 109.10, 100.62, 49.93, 46.64, 44.50, 27.74, 11.55. ESI-HRMScalculated for C 21 H 26 ClN2 + ([M + H)) + ): 341.1779; measured: 341.1791. NMR data for compound 3o: 1 H-NMR (CDCl3, 400 MHz): δ 1.01 (t, J = 7.1 Hz, 6H,CH3), 1.98-2.04 (m, 2H, NCH2CH2), 2.45 (t, J = 7.0 Hz, 2H, NCH2), 2.54 (q, J = 7.2Hz, 4H, NCH2CH3), 4.22 (t, J = 4.7 Hz, 2H, NCH2), 6.60 (d, 1H, J = 2.4 Hz, Indole-H), 7.12-7.64 (m, 8H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101 MHz) δ 143.18, 136.37,134.24, 133.02, 129.66, 128.77, 128.57, 126.94, 126.86, 126.61, 121.69,119.28, 109.16, 100.16, 49.90, 46.64, 44.48, 29.63, 14.13. ESI-HRMScalculated for C 21 H26 ClN2 + ([M + H)) + ): 341.1779; measured: 341.1794. NMR data for compound 3p: 1 H-NMR (CDCl3, 400 MHz): δ 1.01 (t, J = 7.2 Hz, 6H,CH3), 1.98-2.04 (m, 2H, NCH2CH2), 2.45 (t, J = 7.1 Hz, 2H, NCH2), 2.54 (q, J = 7.2Hz, 4H, NCH2CH3), 4.22 (t, J = 7.0 Hz, 2H, NCH2), 6.60 (d, 1H, J = 3.2 Hz, Indole-H), 7.12-7.44 (m, 6H, Ph-H, Indole-H), 7.63 (d, J = 8.6 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 139.74, 136.34, 133.23, 132.71, 130.00, 128.58, 128.49,126.59, 121.73, 119.16, 108.92, 100.20, 49.85, 46.60, 44.44, 27.52, 11.31.ESI-HRMS calculated for C 21 H 26 ClN2 + ([M + H)) + ): 341.1779; measured: 341.1789. NMR data for compound 3q: 1 H-NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.3 Hz, 6H,CH3), 1.27-1.33 (m, 4H, CH2), 1.37-1.42 (m, 4H, NCH2CH2), 1.97-2.04 (m, 2H,NCH2CH2), 2.39-2.48 (m, 6H, NCH2), 4.21 (t,J = 7.1 Hz, 2H, NCH2), 6.66 (dd, J =3.2, 0.7 Hz, 1H, Indole-H), 7.16-7.49 (m, 7H, Ph-H, Indole-H), 7.71 (dd, J =8.2, 1.2 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 141.33, 136.33, 134.57,128.81, 128.41, 128.27, 126.83, 126.78, 121.67, 119.22, 108.61, 100.42,53.66, 51.19, 44.52, 28.97, 27.74, 20.73, 14.10. ESI-HRMS calculated forC 25 H 25 N2 + ([M + H)) + ): 363.2795; measured: 363.2809. NMR data for compound 3r: 1 H-NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 6H,CH3), 1.29-1.33 (m, 4H, CH2), 1.41 (d, J = 6.0 Hz, 4H, NCH2CH2), 1.96-2.03 (m,2H, NCH2CH2), 2.38-2.47 (m, 6H, NCH2), 4.20 (t, J = 7.2 Hz, 2H, NCH2), 6.26 (d, J = 3.1 Hz, 1H, Indole-H), 7.09-7.53 (m, 8H, Ph-H, Indole-H). 13 C NMR (CDCl3, 101MHz) δ139.74, 135.90, 133.18, 131.96, 131.90, 129.76, 128.30, 128.15, 127.62,126.41, 120.96, 120.37, 109.12, 100.57, 53.71, 51.23, 44.56, 29.13, 27.87,20.75, 14.14. ESI-HRMS calculated for C 24 H 24 ClN2 + ([M + H)) + ): 397.2405;measured: 397.2418. NMR data of compound 3s: 1 H-NMR (CDCl3, 500 MHz): δ 0.83 (t, J = 7.3 Hz, 6H,CH3), 1.20-1.24 (m, 4H, CH2), 1.29-1.34 (m, 4H, NCH2CH2), 1.88-1.95 (m, 2H,NCH2CH2), 2.30-2.37 (m, 6H, NCH2), 4.13 (t, J = 7.1 Hz, 2H, NCH2), 6.54 (d, J =3.2, Hz, 1H, Indole-H), 7.06-7.30 (m, 6H, Ph-H, Indole-H), 7.50 (d, J = 7.6 Hz,H, Ph-H), 7.61 (s, 1H, Ph-H). 13 C NMR (CDCl3, 126 MHz) δ 142.20, 135.36, 133.23,131.99, 128.62, 127.76, 127.55, 125.91, 125.81, 125.61, 120.62, 118.23,108.17, 99.07, 52.68, 50.19, 43.51, 28.06, 26.84, 19.71, 13.08. ESI-HRMScalculated for C 24 H 24 ClN2 + ([M + H)) +): 397.2405; measured: 397.2418. NMR data of compound 3t: 1 H-NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 6H,CH3), 1.25-1.32 (m, 4H, CH2), 1.36-1.43 (m, 4H, NCH2CH2), 1.92-2.04 (m, 2H,NCH2CH2), 2.36-2.47 (m, 6H, NCH2), 4.21 (t, J = 7.1 Hz, 2H, NCH2), 6.60 (d, J =3.1 Hz, 1H, Indole-H), 7.12-7.45 (m, 6H, Ph-H, Indole-H), 7.63 (dd, J = 8.8, 2.1 Hz, 2H, Ph-H). 13 C NMR (CDCl3, 101 MHz) δ 139.78, 136.33, 133.23, 132.70,130.01, 128.59, 128.52, 126.60, 121.67, 119.13, 108.97, 100.09, 53.67, 51.18,44.54, 29.04, 27.82, 20.74, 14.12. ESI-HRMS calculated for C 24 H 24 ClN2 + ([M + H)) + ): 397.2405; measured: 397.2412. The N-propyl-4-phenylindole derivatives prepared in Examples 1 and 2 were used as test compounds. The test compounds were systematically evaluated for pharmacology and drug-likeness, including: histamine H3 receptor antagonistic activity assay, mouse anticonvulsant activity assay, zebrafish convulsion inhibition experiment, cytotoxicity test, neurotoxicity test, pharmacokinetic characteristics study and blood-brain barrier penetration ability evaluation.

[0040] 1. Determination of histamine H3 receptor antagonistic activity and histamine H1, H2 and H4 receptor antagonistic activity.

[0041] Stable HEK-293T cells co-transfected with histamine H3 receptor and pCRE-Luc were seeded in 96-well plates overnight and grown to 90%–95% confluence. Cells were then treated with different concentrations of the test compound in serum-free DMEM and cultured for 20 minutes. Serum-free DMEM containing 2 μM Forskolin and 100 nM histamine was then added, and the cells were cultured at 37°C for 4 hours. Luciferase activity was measured using a firefly luciferase assay kit, and the IC50 of the histamine H3 receptor antagonistic activity of the test compound was calculated. 50 The tested compounds were compounds 3a to 3t; the results are shown in Table 2.

[0042] Table 2. Results of histamine H3 receptor antagonistic activity assays for compounds 3a to 3t Note: NT indicates not measured. a This indicates the percentage of antagonism at a concentration of 10 micromoles.

[0043] As shown in Table 2, most compounds exhibited good histamine H3 receptor antagonistic activity. Among them, compounds 3a, 3b, 3g, 3m, and 3n prepared in the embodiments of this invention showed good IC50 activity. 50 The concentrations were 2.531 μM, 2.850 μM, 1.276 μM, 3.212 μM, and 1.877 μM, respectively, showing... out Strong H3R antagonistic activity.

[0044] A luciferase reporter gene assay, similar to that used for the H3 receptor, was employed. Stable HEK-293T cell lines co-transfected with human H1, H2, or H4 receptors and the pCRE-Luc reporter gene were constructed. Cells were seeded in 96-well plates and cultured to 90%–95% confluence. The plates were then replaced with serum-free DMEM, and different concentrations of the test compounds were added for pre-incubation for 20 minutes. Subsequently, 2 μM Forskolin and 1 μM histamine were added, and incubation continued for 4 hours. Fluorescence intensity was measured using a luciferase assay kit, and the IC50 of the antagonistic activity of each compound against different histamine receptor subtypes was calculated. 50 The positive control drugs were cetirizine (H1 antagonist), ranitidine (H2 antagonist), and NJN-7777120 (H4 antagonist).

[0045] Table 3. Results of antagonistic activities of compounds 3a, 3b, 3g, 3m, and 3n against histamine H1, histamine H2, and histamine H4 receptors. Note: NT indicates not measured.

[0046] As shown in Table 3, the compounds of this invention exhibit significant differences in selectivity for different histamine receptor subtypes. Compounds 3a, 3g, 3m, and 3n showed almost no antagonistic activity against H1 and H4 receptors at a concentration of 10 μmol / L (IC50). 50 The concentration >10 μmol / L indicates that it exhibits good subtype selectivity for the H3 receptor. Notably, compounds 3g and 3m show strong antagonistic activity against the H2 receptor (IC50). 50 The concentrations were 0.697 μmol / L and 0.484 μmol / L, respectively, suggesting a possible dual regulatory effect. Compounds 3b and 3n exhibited strong antagonistic activity against the H1 receptor (IC50). 50 The concentrations were 2.318 μmol / L and 6.934 μmol / L, respectively, but there was no significant activity against the H2 and H4 receptors. Overall, the compounds of the present invention, especially compound 3a, maintain strong H3 receptor antagonistic activity while exhibiting activity against the H1 receptor. 、 H2 and H4 receptors have good selectivity, which helps reduce non-target-related side effects and has the potential for further development.

[0047] 2. Anticonvulsant activity assay in mice and convulsion inhibition experiment in zebrafish.

[0048] Anticonvulsant activity assay in mice: The efficacy of the test compounds against generalized epileptic seizures was determined using a maximal electroconvulsive seizure (MES) model. The test compounds were administered intraperitoneally to mice to inhibit or delay seizures. The test compounds were compounds 3a, 3b, 3m, and 3n; the MES model was a maximal electroconvulsive seizure model.

[0049] The specific method was as follows: Kunming mice weighing 18g-22g were randomly divided into several experimental groups, with 6 mice in each group. Different doses of the test compound were injected intraperitoneally into each experimental group. At 0.5 hours and 4 hours after administration, electrical stimulation (60Hz AC, 50mA, stimulation duration 0.2 seconds) was applied via ear clip electrodes using an electroconvulsive device to induce tonic-clonic seizures in the mice. Whether the mice exhibited tonic extension of the hind limbs after electrical stimulation was observed and recorded. Mice that did not exhibit hind limb rigidity after electrical stimulation were defined as "protected." The number of protected animals in each group was counted, and the results are shown below. Figure 2 Subsequently, multiple-dose tests were performed on compounds that showed protective effects, and their median effective dose (ED) was calculated using a modified Koch method. 50 The results are shown in Table 4.

[0050] Table 4. ED of the test compounds in MES model testing 50 value Note: ED 50This indicates the median effective dose, which is the effective dose required to induce antiepileptic protection in 50% of experimental animals. ED 50 It is an important indicator for measuring the anticonvulsant activity of drugs; the lower the value, the stronger the drug's efficacy.

[0051] like Figure 2 As shown, compounds 3a, 3b, 3m, and 3n all antagonized MES-induced seizures to varying degrees 4 hours after administration, and were significantly superior to the positive control drug sodium valproate. The effects of ED5 on compounds 3a, 3b, 3m, and 3n were also observed. 50 The values ​​were 23.53 mg / kg, 27.38 mg / kg, 19.02 mg / kg and 16.44 mg / kg, respectively (Table 4).

[0052] To further evaluate the anticonvulsant activity of the target compound, a zebrafish seizure model induced by pentylenetetrazole (PTZ) was used for validation. This model, which induces excessive movement in juvenile zebrafish to mimic seizures in mammals, is commonly used for the initial screening of antiepileptic drugs.

[0053] The specific method was as follows: Six-day-old AB strain zebrafish juveniles were selected and placed in 48-well plates (one fish per well). They were pre-incubated for 3 hours with different concentrations (0 μmol / L, 1 μmol / L, 2 μmol / L, 3 μmol / L, and 4 μmol / L) of the test compound or carbamazepine (0 μmol / L, 100 μmol / L, 125 μmol / L, and 150 μmol / L). Subsequently, PTZ at a final concentration of 10 mmol / L was added to induce convulsions, and the total distance the zebrafish moved within 40 minutes was recorded. The movement behavior was automatically tracked and analyzed using a zebrafish behavior analysis system. The test compounds were compounds 3m and 3n.

[0054] Depend on Figure 3The results showed that both compounds 3m and 3n inhibited PTZ-induced excessive movement in zebrafish in a concentration-dependent manner, exhibiting significant anticonvulsant activity. Compared with the PTZ-treated control group (total movement distance: 10539.53±2250.42 mm), compound 3m showed a progressively more significant effect with increasing concentration, reaching its most significant effect at 10 μM (total movement distance: 323.649±186.86 mm, a 96.03% reduction in movement distance), significantly shortening the total movement distance of zebrafish. Similarly, compared with the PTZ-treated control group (total movement distance: 10884.343±1143.795 mm), compound 3n showed a progressively more significant effect with increasing concentration, reaching its most significant effect at 10 μM (total movement distance: 145.57±118.86 mm, a 98.66% reduction in movement distance), significantly shortening the total movement distance of zebrafish. In summary, compounds 3m and 3n exhibit significantly superior anticonvulsant activity compared to the classic antiepileptic drug carbamazepine, even at concentrations far below the effective concentration of carbamazepine (150 μM). This demonstrates that compounds 3m and 3n, as H3R-targeted antiepileptic candidates, possess superior activity potential and application advantages, providing strong support for their future development.

[0055] 3. Cytotoxicity and neurotoxicity tests of the compounds.

[0056] Cytotoxicity assay: The in vitro cytotoxicity of the test compounds to nerve cells was determined using the CCK-8 assay; the test compounds were compound 3m and compound 3n.

[0057] The specific method was as follows: SH-SY5Y cells and PC12 cells were placed in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin and cultured at 37°C in a 5% CO2 cell culture incubator. Once the cell density reached a certain level, they were seeded at a density of 10,000 cells per well in 96-well plates. After incubation for 24 hours, the cells were placed in serum-free medium with different concentrations of compounds 3M and 3N added, and cultured for another 24 hours at 37°C. Wells without added compounds served as control wells. After adding 10 μL / well of CCK-8 and incubating in the dark for 1 hour, the absorbance at 450 nm was measured using a microplate reader, and cell viability was calculated. Results are shown below. Figure 4 .

[0058] Depend on Figure 4 Results A showed that, within the concentration range of 5 μM to 100 μM, compounds 3m and 3n maintained cell viability above 60% in SH-SY5Y cells at all concentration groups. Figure 4In PC12 cells, the survival rates of both compounds at concentrations ≤40 μM were similar to those of the control group, and they showed low toxicity at a concentration of 100 μM. Compounds 3m and 3n showed no significant cytotoxicity to SH-SY5Y and PC12 cells within their effective concentration range, exhibiting good cellular safety characteristics. This provides reliable toxicity data to support their further development as antiepileptic candidate compounds, making them suitable for advancing to the in vivo activity and safety evaluation stage.

[0059] Neurotoxicity test: The in vivo neurotoxicity of the test compounds was evaluated using the rotating bar method. The specific method for in vivo neurotoxicity determination was as follows: Kunming mice weighing 18g–22g were injected intraperitoneally with the test compound. Half an hour later, the mice were placed on a 1-inch diameter corrugated cylinder rotating at 6 rpm. Mice that could maintain balance for 1 minute without falling off the cylinder in three consecutive experiments were considered neurotoxically negative; otherwise, they were considered neurotoxically positive. The test compounds were compounds 3a, 3b, 3m, and 3n; the results are shown in Table 5.

[0060] Table 5. Neurotoxicity test results of the test compounds in the rotating bar test. Note: The results of the rotator bar test are expressed as the number of animals with neurotoxicity / the number of test animals.

[0061] Table 5 shows that no neurotoxic signs were observed in mice treated with the test compounds at doses of 30 mg / kg and 100 mg / kg. These results indicate that compounds 3a, 3b, 3m, and 3n have good safety profiles at therapeutic dose levels.

[0062] 4. Pharmacokinetic characteristics of compounds.

[0063] To evaluate the in vivo metabolism and oral drugability of the target compound 3n, pharmacokinetic studies were conducted in rats.

[0064] Experimental methods: Healthy SD rats were randomly divided into an intravenous injection group (2 mg / kg) and an oral gavage group (10 mg / kg), with 5 rats in each group. Plasma samples were collected at multiple time points after drug administration, and the concentration of compound 3n in the plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The main pharmacokinetic parameters were calculated using specialized software and are shown in Table 6.

[0065] Table 6. Major pharmacokinetic parameters of compound 3n in rats As shown in Table 6 and Figure 5 As shown, the elimination half-life (T0) of compound 3n after intravenous administration... 1 / 2The time to peak concentration (Tc) was 6.878 ± 2.725 h, indicating a moderate retention time in the body. After oral administration, the time to peak concentration (Tc) was... max The peak concentration (C) was 2h. max The effective dose was 2126.427 ± 370.187 ng / mL. The area under the curve (AUC) for oral administration was... 0→∞ The concentration of the compound was 30358.737±9707.04 μg·h / L, and its absolute oral bioavailability (F) was calculated to be 60.73%, indicating that compound 3n has good oral absorption potential and its oral dosage form has the basis for further development.

[0066] 5. Evaluation of the blood-brain barrier penetration ability of compounds.

[0067] Given that epilepsy treatment drugs need to act on the central nervous system, the ability of compound 3n to penetrate the blood-brain barrier (BBB) ​​was evaluated.

[0068] Experimental methods: Rats were intravenously injected with compound 3n (2 mg / kg), and sacrificed at 30, 60, and 90 minutes. Plasma and whole brain tissue were collected simultaneously. After homogenization, the brain tissue and plasma samples were analyzed by LC-MS / MS to determine the drug concentration, and the brain / plasma ratio was calculated at each time point. The results are shown in Table 7.

[0069] Table 7. Brain distribution of compound 3n in rats (mean ± SD, n=3) As shown in Table 7 and Figure 6 As shown, at 30, 60, and 90 minutes after administration, the intracerebral concentration of compound 3n was significantly higher than its plasma concentration at the same time, with brain-to-plasma concentration ratios of 0.65, 1.53, and 1.16, respectively. This indicates that compound 3n can rapidly and effectively penetrate the blood-brain barrier and accumulate in brain tissue (reaching its maximum concentration at 60 minutes). This excellent BBB penetration characteristic is the key pharmacokinetic basis for its ability to exert histamine H3 receptor antagonistic effects and anticonvulsant activity in the central nervous system, further supporting its potential as a novel antiepileptic drug candidate.

[0070] It should be noted that when numerical ranges are involved in this invention, it should be understood that the two endpoints of each numerical range, as well as any value between the two endpoints, can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described in this invention to avoid redundancy. Although preferred embodiments of this invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments, and all such changes and modifications fall within the scope of this invention.

[0071] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. If these modifications and variations fall within the scope of equivalents of this invention, then this invention also intends to include these modifications and variations.

Claims

1. An N-propyl-4-phenylindole derivative, characterized in that, The chemical structural formula of the N-propyl-4-phenylindole derivative is as follows: ； In the formula, R1 is H or a halogen; R2 is selected from any of the following groups: 。 2. The N-propyl-4-phenylindole derivative according to claim 1, characterized in that, The N-propyl-4-phenylindole derivative is selected from one of the following compounds: 。 3. A method for preparing the N-propyl-4-phenylindole derivative according to claim 1 or 2, characterized in that, Includes the following steps: 4-Bromo-1H-indole was subjected to a Suzuki coupling reaction with a phenylboronic acid compound to give intermediate 2; Intermediate 2 was subjected to an N-alkylation reaction with a chloropropylamine reagent to yield an N-propyl-4-phenylindole derivative; the synthetic route is as follows: 。 4. The method for preparing the N-propyl-4-phenylindole derivative according to claim 3, characterized in that, Benzylboronic acid compounds include phenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, or 4-chlorophenylboronic acid; Chloropropylamine reagents include N-(3-chloropropyl)piperidine hydrochloride, 4-(3-chloropropyl)morpholine, 3-chloro-N,N-diethylpropyl-1-amine, N-(3-chloropropyl)dibutylamine, or 1-(3-chloropropyl)-4-phenylpiperidine.

5. The method for preparing the N-propyl-4-phenylindole derivative according to claim 3, characterized in that, The specific preparation method of intermediate 2 is as follows: 4-Bromo-1H-indole, a phenylboronic acid compound, a base, and a palladium catalyst were dissolved in a solvent, and a Suzuki coupling reaction was carried out to give intermediate 2.

6. The method for preparing the N-propyl-4-phenylindole derivative according to claim 5, characterized in that, The molar ratio of 4-bromo-1H-indole, phenylboronic acid compounds, and base is 1:1.1–1.3:2–4; the molar ratio of 4-bromo-1H-indole to palladium catalyst is 1:0.02–0.

1.

7. The method for preparing the N-propyl-4-phenylindole derivative according to claim 3, characterized in that, The molar ratio of intermediate 2 to chloropropylamine reagent is 1:1 to 1.

2.

8. The method for preparing the N-propyl-4-phenylindole derivative according to claim 3, characterized in that, The temperature for the Suzuki coupling reaction is 60℃~70℃; the temperature for the N-alkylation reaction is 80℃~90℃.

9. The method for preparing the N-propyl-4-phenylindole derivative according to claim 3, characterized in that, The solvent is 1,4-dioxane and water, with a volume ratio of 1,4-dioxane to water of 3:1; the base is potassium carbonate.

10. The use of an N-propyl-4-phenylindole derivative in the preparation of drugs for treating epilepsy, characterized in that, The N-propyl-4-phenylindole derivative is the N-propyl-4-phenylindole derivative according to claim 1 or 2.

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