Drug for treating seizure disorders and its preparation method

Abstract

The present invention provides a drug for treating seizure disorders and a preparation method thereof. The drug is a tanshinone IIA analogue having the structure of Formula I. The tanshinone IIA analogue of the present invention can well inhibit epilepsy, reduce the number of seizures, shorten the duration of epilepsy, and can reduce the level of homocysteine in the body and reduce the damage of nerve function. In addition, the pharmacological activity of the compound of the present invention is superior to that of tanshinone IIA. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to a drug for treating seizure disorders and a method for preparing the same. Background Art

[0002] Epilepsy is a common neurological disorder characterized by transient disturbances in brain function caused by abnormal electrical discharges of brain neurons. Patients may present with sensory, motor, consciousness, mental, behavioral, autonomic dysfunction or a combination thereof, which poses risks to social, physical and mental health. The diagnosis of epilepsy is mainly based on clinical manifestations, and auxiliary investigations include electroencephalogram and neuroimaging, with magnetic resonance imaging being the main one. The second criterion for judgment is motor or non-motor seizure symptoms. The third criterion is whether there is impairment of consciousness during the seizure.

[0003] For the first-line treatment of epilepsy, the "Guidelines for the Evaluation and Management of Status Epilepticus" issued by the American Society of Neurocritical Care, the "Treatment of Convulsive Status Epilepticus in Children and Adults" issued by the American Epilepsy Society, and the "Expert Consensus on the Treatment of Non-convulsive Status Epilepticus" issued by the Chinese Medical Association all recommend intravenous infusion of benzodiazepines as the first choice. However, the effective rate is only about 70%. For patients who fail first-line treatment, the second-line treatment drugs recommended in the "Treatment of Convulsive Status Epilepticus in Children and Adults" are limited to phenytoin (PHT), fosphenytoin (FPHT), valproate (VPA), levetiracetam (LEV), etc. However, the side effects of these drugs are difficult to control and some patients cannot tolerate them, and they are prone to the occurrence of drug-resistant epilepsy.

[0004] Traditional Chinese medicine has the advantages of less side effects and reducing the occurrence of epilepsy complications. In recent years, many literatures have reported the effects of traditional Chinese medicine monomer compounds and traditional Chinese medicine extracts in the treatment of epilepsy. Mechanistically, they generally include: 1. Regulating ion channels, such as rhynchophylline (Anticonvulsant effect of Rhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epilepsy. Shao H, et al. Neuroscience, 2016, 337:355-369), saikosaponin A (Saikosaponin a modulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporal lobe epilepsy. Hong Y, et al. Drug Design, Development and Therapy, 2018, 12:2945-2958), tanshinone IIA (Tanshinone IIA, a constituent of Danshen, inhibits the release of glutamate in rat cerebrocortical nerve terminals. Lin T Y, et al. Journal of Ethnopharmacology, 2013, 147(2):488-496), tetramethylpyrazine (Tetramethylpyrazine reduces epileptogenesis progression in electrical kindling models by modulating hippocampal excitatory neurotransmission. Jin Y, et al.ACS Chemical Neuroscience, 2019, 10(12): 4854 - 4863), Gastrodin reduces the severity of status epilepticus in the rat pilocarpine model of temporal lobe epilepsy by inhibiting Nav1.6 sodium currents. Shao H, et al. Neurochemical Research, 2017, 42(2): 360 - 374), etc.; 2. Antioxidant stress types, such as baicalin (Hu Yugang. The effect of baicalin on the expression of HO - 1 and NQO1 in the hippocampal tissue of kainic acid - induced epileptic mice. Fuzhou: Master's thesis of Fujian Medical University, 2015), salidroside (Salidroside shows anticonvulsant and neuroprotective effects by activating the Nrf2 - ARE pathway in a pentylenetetrazol - kindling epileptic model. Wu Y, et al. Brain Research Bulletin, 2020, 164: 14 - 20), paeonol (Anticonvulsant and neuroprotective effects of paeonol in epileptic rats. Liu D H, et al. Neurochemical Research, 2019, 44(11): 2556 - 2565.), emodin (The protective effect of emodin on hippocampal neurons in kainic acid - induced epileptic mice. Ouyang Longqiang, etc. International Journal of Neurology and Neurosurgery, 2018, 45(5): 471 - 476.), glycyrrhizic acid (Glycyrrhizic acid protects juvenile epileptic rats against hippocampal damage through activation of Sirtuin3. Wu G, et al. Brain Research Bulletin, 2020, 164: 98 - 106), taurine (Taurine protects from pentylenetetrazole - induced behavioral and neurochemical changes in Zebrafish.Fontana B D, et al. Molecular Neurobiology, 2019, 56(1): 583 - 594, etc.; 3. Protect neuronal cells, such as Hyperoside (Hyperoside alleviates epilepsy - induced neuronal damage by enhancing antioxidant levels and reducing autophagy. Cao J, et al. Ethnopharmacol, 2020, 257: 112884), ethanol extract of scorpion (Scorpion ethanol extract and valproic acid effects on hippocampal glial fibrillary acidic protein expression in a rat model of chronic - kindling epilepsy induced by lithium chloride - pilocarpine. Liang Y, et al. Neural Regeneration Research, 2012, 7(6): 426 - 433), etc.; 4. Inhibit neuronal cell apoptosis, such as Ginsenoside (Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2 / ARE Signaling. Shi Y, et al. Cellular Physiology and Biochemistry, 2018, 45(1): 212 - 225), Puerarin (Research progress of Puerarin. Wang Donghong, etc. West China Journal of Traditional Chinese Medicine, 2017, 30(1): 139 - 142), Osthole (Effect of Osthole on the expression of Caspase - 3 and Caspase - 9 proteins in neurons of kainic acid - induced epileptic rats. Xie Hongting, etc. Information on Traditional Chinese Medicine, 2015, 32(2): 16 - 18), volatile oil of Acorus tatarinowii (Anticonvulsant effect of volatile oil of Acorus tatarinowii and its effect on the expression of PKC in the hippocampus of epileptic rats. Wang Kunfang, etc. Pharmacology and Clinics of Chinese Materia Medica, 2015, 31(1): 97 - 100), etc.

[0005] The monomeric compounds of traditional Chinese medicine provide new ideas for exploring the treatment plan of epilepsy. Summary of the Invention

[0006] The object of the present invention is to provide a compound with improved epilepsy treatment effect, and the compound is a tanshinone IIA analogue.

[0007] In one aspect of the present invention, the present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof:

[0008]

[0009] Wherein:

[0010] X is selected from CR0, N;

[0011] R0 represents H, (C1-6) alkyl, (C1-6) alkoxy.

[0012] R1 and R2 are each independently selected from H, optionally substituted (C1-6) alkyl, optionally substituted (C1-6) alkoxy.

[0013] In one embodiment, X is selected from CH.

[0014] In one embodiment, X is selected from N.

[0015] In one embodiment, the optional substitution means being substituted or unsubstituted by one or more groups selected from the following groups: halogen, hydroxyl, amino.

[0016] In one embodiment, R1 and R2 are each independently selected from H, (C1-4) alkyl.

[0017] Preferably, R1 is selected from H.

[0018] Preferably, R2 is selected from methyl, ethyl.

[0019] In one embodiment, the compound is selected from:

[0020]

[0021] In the present invention, halogen means fluorine, chlorine, bromine or iodine.

[0022] In the present invention, alkyl means a straight-chain or branched-chain saturated hydrocarbon group preferably containing 1-6 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl, etc.

[0023] In one embodiment, the pharmaceutically acceptable salt of the compound of the present invention refers to a pharmaceutically acceptable acid addition salt, including: hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, malonate, succinate, tartrate, citrate, oxalate, mesylate or p-toluenesulfonate, etc., but not limited thereto.

[0024] In the present invention, a solvate of the compound of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0025] In another aspect of the present invention, the present invention provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt, solvate thereof.

[0026] In one embodiment, the pharmaceutical composition of the present invention may comprise one or more pharmaceutically acceptable carriers.

[0027] The pharmaceutical composition of the present invention can be administered in a standard manner for the condition to be treated, for example, by topical, oral, rectal, or parenteral administration. To achieve the above object, the compound of the present invention can be formulated in a known manner in the art into, for example, an aerosol, a dry powder preparation, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories, ointments, creams, drops, and sterile aqueous or oily solutions or suspensions.

[0028] Depending on the mode of administration, the pharmaceutical composition may contain 0.05 - 99 wt%, for example 0.05 - 80 wt%, for example 0.10 - 70 wt%, for example 0.10 - 50 wt% of the active ingredient, all weight percentages being calculated based on the entire composition. The suitable pharmaceutical composition of the present invention is suitable for oral administration in unit dosage forms, for example, in the form of tablets or capsules for oral administration, wherein each tablet contains 0.1 mg - 0.2 g of the active ingredient.

[0029] The present invention provides a method for preparing the composition, the method comprising mixing the active ingredient with a carrier.

[0030] The effective dose of the compound of the present invention can be determined according to age, body weight, gender, administration method, health condition, and severity of the disease. For example, the dose for an adult weighing 70 kg is 0.1 - 1000 mg / day, preferably 1 - 500 mg / day. Such administration can be carried out once to multiple times a day, according to the decision of a doctor or a pharmacist.

[0031] In another aspect of the present invention, the present invention also provides the use of the compound of formula I or a pharmaceutically acceptable salt, solvate thereof in the preparation of a drug for preventing or treating epilepsy.

[0032] In another aspect of the present invention, the present invention also provides a method for preparing a compound of formula I, which comprises the following steps:

[0033]

[0034] The raw material a is converted into an intermediate b containing a boric acid ester or a boric acid, and then undergoes a coupling reaction with the raw material c to obtain an intermediate d; the intermediate d is cyclized to form a compound of formula I;

[0035] wherein R1-R2, X are as described above, Xa, Xb are each independently selected from chlorine or bromine, Ra, Rb are each independently selected from (C1-4) alkyl, R B Selected from

[0036] Beneficial effects

[0037] The present invention provides a drug for treating epileptic seizures. Using Tanshinone IIA as a lead compound, the present invention designs and synthesizes Tanshinone IIA analogs. These compounds inhibit epilepsy, reducing the frequency and duration of seizures, and can lower homocysteine levels in the body, reducing neurological damage. Furthermore, the compounds of the present invention demonstrate significantly superior efficacy to Tanshinone IIA in treating epilepsy, surpassing the lead compound. DETAILED DESCRIPTION

[0038] The present invention is described in more detail below to facilitate understanding of the present invention.

[0039] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0040] Example 1:

[0041]

[0042] Synthesis of Intermediate 1-b: Under nitrogen, 1-a (4.76 g, 20 mmol), B2Pin2 (6.09 g, 24 mmol), K2CO3 (5.53 g, 40 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.29 g, 0.4 mmol) were added to 1,4-dioxane (50 mL). The reaction mixture was heated under reflux with stirring for 4 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 × 50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was recrystallized from 95% ethanol and dried to afford Intermediate 1-b (4.67 g, 82% yield); ESI-MS: 286.22 [M+H] + .

[0043] Synthesis of Intermediate 1-d: Under nitrogen protection, 1-b (2.85 g, 10 mmol), 1-c (2.09 g, 12 mmol), K2CO3 (2.77 g, 20 mmol), and Pd(PPh3)4 (0.23 g, 0.2 mmol) were added to 100 mL of a mixed solvent of toluene / ethanol / water (2:1:1). The above reaction system was heated to reflux for 5 h. After the reaction was completed, it was naturally cooled to room temperature, 100 mL of distilled water was added, and it was extracted with dichloromethane (150 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase petroleum ether:ethyl acetate = 10:1), and dried to obtain Intermediate 1d (2.32 g, 78%); ESI-MS: 298.24 [M+H] + .

[0044] Synthesis of Compound 1: Under nitrogen protection, Intermediate 1d (1.49 g, 5 mmol) was dissolved in dry dichloromethane (50 mL). After cooling to -78 °C, BBr3 (1.0 M in dichloromethane, 10 mmol) was added dropwise thereto. The reaction system was warmed to 0 °C and stirred for 1.5 h, and water (50 mL) was carefully added. Then the reaction system was stirred at room temperature for 1 h and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase petroleum ether:ethyl acetate = 30:1 - 5:1), and dried to obtain Compound 1 (1.16 g, 92%). ESI-MS: 252.11 [M+H] + ; Elemental analysis: Theoretical values, C, 71.71; H, 3.61; N, 5.58; O, 19.10; Measured values for C 15 H9NO3, C, 71.67; H, 3.65; N, 5.54; O, 19.12. 1 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 7.8, Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.48 (5, J = 7.8 Hz, 1H), 6.91 (s, 1H), 2.46 (s, 3H).

[0045] Example 2:

[0046]

[0047] Synthesis of Intermediate 2-b: Under nitrogen protection, 2-a (3.89 g, 20 mmol), B2Pin2 (6.09 g, 24 mmol), K2CO3 (5.53 g, 40 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.29 g, 0.4 mmol) were added to 1,4-dioxane (50 mL). The above reaction system was heated under reflux with stirring for 5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 × 50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was recrystallized from 95% ethanol and dried to obtain Intermediate 2-b (4.52 g, yield 79%); ESI-MS: 287.17 [M+H] + .

[0048] Synthesis of Intermediate 2-d: Under nitrogen protection, 2-b (2.86 g, 10 mmol), 1-c (2.09 g, 12 mmol), K2CO3 (2.77 g, 20 mmol), and Pd(PPh3)4 (0.23 g, 0.2 mmol) were added to a mixed solvent of 100 mL of toluene / ethanol / water (2:1:1). The above reaction system was heated under reflux for 7 h. After the reaction was completed, it was naturally cooled to room temperature, distilled water (100 mL) was added, and it was extracted with dichloromethane (150 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase petroleum ether: methanol = 10:1), dried to obtain Intermediate 1d (2.20 g, 74%); ESI-MS: 299.12 [M+H] + .

[0049] Synthesis of Compound 2: Under nitrogen protection, Intermediate 2d (1.49 g, 5 mmol) was dissolved in dry dichloromethane (50 mL). After cooling to -78 °C, BBr3 (1.0 M in dichloromethane, 10 mmol) was added dropwise thereto. The reaction system was warmed to 0 °C and stirred for 2 h, and water (50 mL) was carefully added. Then the reaction system was stirred at room temperature for 1 h and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase petroleum ether: ethyl acetate = 15:1 - 3:1), dried to obtain Compound 2 (1.13 g, 90%). ESI-MS: 253.26 [M+H] + ; Elemental analysis: Theoretical value C 14H8N2O3, C, 66.67; H, 3.20; N, 11.11; O, 19.03; Found: C, 66.63; H, 3.22; N, 11.14; O, 19.00. 1 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 7.8 Hz, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 6.93 (s, 1H), 2.46 (s, 3H).

[0050] Test Example:

[0051] 1. Materials

[0052] A total of 48 healthy male SD rats, 10 weeks old and weighing 200 - 250 g, were selected. All rats were kept under the same feeding conditions and placed in the same laboratory 1 week before the experiment, with free movement and access to food and water. The test drugs were prepared as in Examples 1 and 2, and tanshinone IIA was used as a control. The rat homocysteine ELISA kit was purchased from Hepeng (Shanghai) Biotechnology Co., Ltd.

[0053] 2. Methods

[0054] Forty freely - fed SD rats were intraperitoneally injected with lithium chloride (127 mg / kg). After 24 h, they were intraperitoneally injected with pentylenetetrazol (35 mg / kg). Half an hour after the injection of pentylenetetrazol, the rats were observed for symptoms such as chewing and nodding, facial muscle twitching, limb clonus, and falling. According to the Racine grading evaluation standard, it was divided into 5 grades: Grade I: Facial clonus; Grade II: Rhythmic nodding; Grade III: Unilateral forelimb twitching; Grade IV: Bilateral forelimb twitching; Grade V: Limb twitching, loss of balance, jumping, and falling. If epileptic seizures of Grade IV and V occurred and lasted for half an hour, status epilepticus could be diagnosed. If the rats continuously showed Grade IV - V manifestations during the modeling process, it indicated successful modeling. Finally, 35 rats with successful modeling and survival were selected, and 32 of them were randomly divided into 4 groups, including a model group, Compound 1, Compound 2, and tanshinone IIA groups. Among them, Compound 1, Compound 2, and the tanshinone IIA group were respectively given drugs by gavage at a dose of 40 mg / kg·d. Another 8 rats without modeling were used as a normal group. The normal group and the model group rats were gavaged with an equal volume of normal saline (10 mL / kg). Once a day for 14 consecutive days.

[0055] 3. Test of learning and memory ability

[0056] Using the Mois water maze (Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainite induced epilepsy. Grabenstatter H L, et al. Epilepsia, 2010, 46(1):8-14), in a circular pool with a height of 0.5 m, a diameter of 1.25 m, and a water depth of 0.3 m (water temperature 26.5 ± 0.8 °C), four different landmark points were set on the pool wall, and a dark platform with a diameter of 9 cm and a height of 28 cm was set in the center of the pool. The top of the platform was 1.5 cm below the water surface. The external reference in the water maze remained unchanged during the training and testing periods. The training lasted for 5 days. Rats were placed into the pool with the four landmark points as the entry points respectively, and the time taken for the rats to swim to the platform was recorded. If the rats did not find the platform within 120 seconds, they were manually guided to the platform, and the latency was recorded as 120 seconds. After all rats reached the platform, they stayed for a maximum of 30 seconds, and then were placed into the water from different landmark points for testing. The test was conducted continuously for 4 days. On the 5th day, the platform in the water was removed, and the rats were placed into the water from the pool wall, and the number of times the rats crossed the original platform position within 60 seconds was recorded.

[0057] 4. Seizure conditions

[0058] The epileptic rats in the model group and the drug administration group were observed separately. The seizure frequency of the rats and the duration of each seizure were recorded, and comparisons between groups were made.

[0059] 5. Detection of homocysteine level in rat hippocampal tissue

[0060] Hippocampal tissue of rats with a size of 1 cm × 1 cm was taken and stored in a refrigerator at -50 °C. It was taken out before use, centrifuged to obtain the supernatant, and the high performance liquid chromatography method was used. Strictly following the operation steps in the ELISA kit instructions, the measured homocysteine levels were analyzed comparatively.

[0061] 6. Result analysis

[0062] Statistical processing was performed using SPSS 22.0 statistical software. Measurement data were expressed as mean ± standard deviation (—x ± s), and F test was used for comparisons between multiple groups. The test level was α = 0.05, and P < 0.05 was considered statistically significant.

[0063] a. Overall situation

[0064] During the seizure period, epileptic model rats showed increased excitability, rapid breathing, foaming at the mouth, unsteady standing, and limb convulsions.

[0065] b. Spatial learning and memory ability

[0066] As can be seen from the results in Table 1, the escape latency of the rats in the model group was significantly longer than that in the normal group, and the number of platform crossings was significantly less than that in the normal group, indicating successful modeling. The escape latency of the rats in Compound 1 group and Compound 2 group was significantly shorter than that in the model group and also shorter than that in the Tanshinone IIA group. The number of platform crossings was more than that in the model group and also more than that in the Tanshinone IIA group, indicating that Compound 1 group and Compound 2 group had significant effects in improving the spatial learning and memory ability of epileptic rats and were superior to Tanshinone IIA.

[0067] Table 1: Comparison of spatial learning and memory ability

[0068]

[0069] Note: Compared with the normal group, * P < 0.05, ** P < 0.01, *** P < 0.001; compared with the model group, # P < 0.05, ## P < 0.01, ### P < 0.001; compared with the Tanshinone IIA group, & P < 0.05, && P < 0.01

[0070] c. Comparison of epileptic seizure conditions

[0071] As can be seen from the results in Table 2, the duration and frequency of epileptic seizures in the rats of Compound 1 group and Compound 2 group were significantly lower than those in the model group and also lower than those in the Tanshinone IIA group, indicating that Compound 1 group and Compound 2 group had significant effects in improving the epileptic conditions of epileptic rats and were superior to Tanshinone IIA.

[0072] Table 2: Comparison of epileptic seizure conditions

[0073]

[0074] Note: Compared with the model group, ## P < 0.01, ### P < 0.01; compared with the Tanshinone IIA group, && P < 0.01

[0075] d. Comparison of homocysteine levels

[0076] Homocysteine is a sulfur-containing amino acid, an intermediate metabolite of methionine, and belongs to excitatory amino acids. As an excitatory neurotransmitter, homocysteine further induces epileptic seizures and exacerbates epileptic symptoms by stimulating nerve conduction in brain endothelial cells and increasing the permeability of endothelial cell membranes. As can be seen from the results in Table 3, the homocysteine level in the normal group of rats was relatively low, but it was significantly increased in the model group of rats. Compounds 1 and 2, however, had the effect of reducing the homocysteine level, and were significantly superior to the tanshinone IIA group.

[0077] Table 3: Comparison of homocysteine levels

[0078]

[0079] Note: Compared with the normal group, *** P < 0.001; compared with the model group; # P < 0.05, ## P < 0.01; compared with the tanshinone IIA group, & P < 0.05

[0080] Generally speaking, the compounds of the present invention have the effects of inhibiting epilepsy, reducing the number of attacks, shortening the duration, and can also reduce the level of homocysteine in the body and reduce the damage to nerve function.

[0081] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the method of the present invention, several improvements and supplements can still be made, and these improvements and supplements should also be regarded as the protection scope of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: ； Wherein: X is selected from N; R1 and R2 are each independently selected from H, (C1-6) alkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 and R2 are each independently selected from H, (C1-4) alkyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from H; R2 is selected from methyl, ethyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound is selected from: 。 5. A pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4.

6. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4 in the preparation of a medicament for preventing or treating epilepsy.

7. A method for preparing the compound of formula I as claimed in claim 1, which comprises the following steps: ； Converting raw material a into intermediate b containing borate or boric acid, and then carrying out a coupling reaction with raw material c to obtain intermediate d; Intermediate d is cyclized to form a compound of formula I; wherein R1-R2 and X are as described in claim 1, Xa and Xb are each independently selected from chlorine or bromine, Ra and Rb are each independently selected from (C1-4) alkyl, and R B is selected from or .

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