CN116987091A - Medicine for treating epileptic seizure disease and preparation method thereof - Google Patents

Medicine for treating epileptic seizure disease and preparation method thereof Download PDF

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CN116987091A
CN116987091A CN202310950772.0A CN202310950772A CN116987091A CN 116987091 A CN116987091 A CN 116987091A CN 202310950772 A CN202310950772 A CN 202310950772A CN 116987091 A CN116987091 A CN 116987091A
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compound
formula
pharmaceutically acceptable
solvate
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高雨田
王春红
房丽
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Jiamusi University
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Jiamusi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Abstract

The invention provides a medicament for treating epileptic seizure diseases and a preparation method thereof. The medicine is tanshinone IIA analogue with a structure shown in a formula I. The tanshinone IIA analogue provided by the invention can well inhibit epilepsy, reduce the incidence frequency, shorten the duration of epilepsy, reduce the level of homocysteine in vivo and reduce the damage of nerve functions. In addition, the pharmacological activity of the compound of the invention is superior to that of tanshinone IIA.

Description

Medicine for treating epileptic seizure disease and preparation method thereof
Technical Field
The invention relates to the field of medicines, in particular to a medicine for treating epileptic seizure diseases and a preparation method thereof.
Background
Epilepsy is a common neurological disorder characterized by transient malfunctions of brain function caused by abnormal discharges of brain neurons, which may manifest as sensory, motor, conscious, mental, behavioral, autonomic dysfunction or both, with a risk to social, physical and psychological health. Diagnosis of epilepsy is mainly based on clinic, and auxiliary investigation comprises electroencephalogram and neuroimaging, wherein magnetic resonance imaging is mainly adopted. The second criterion is motor or non-motor seizure symptoms. The third criterion is whether the episode is conscious impaired.
For the first-line treatment of epilepsy, the first-choice intravenous infusion of benzodiazepines is recommended by the national institute of intensive care for epilepsy (SOP) and the treatment of status epilepticus for children and adults (SOP) by the American society of epilepticus, and the therapeutic expert consensus of status epilepticus for non-convulsive, which are issued by the China medical society, however, the effective rate is only about 70%. For patients who fail first-line therapy, the second-line therapy recommended in the treatment of status epilepticus in children and adults is limited to Phenytoin (PHT), fosphenytoin (FPHT), valproate (VPA), levetiracetam (LEV), and the like. However, the side effects of these drugs are difficult to control and are not tolerated by some patients and are prone to the development of drug-resistant seizures.
The traditional Chinese medicine has the advantages of small side effect and reduction of epileptic complication attacks, and in recent years, various documents report that the traditional Chinese medicine monomer compounds and traditional Chinese medicine extracts have effects on treating epilepsia, and the traditional Chinese medicine extracts mainly comprise the following components in terms of mechanism: 1. regulatory ion channel classes such as rhynchophylline (Anticonvulsant effect ofRhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epiepsy. Shao H, et al, neuroscience,2016, 337:355-369), saikosaponin A (Saikosaponin amodulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporallobe epiepsy. Hong Y, et al, drug Design, development and Therapy,2018, 12:2945-2958), tanshinone IIA (a constituent of Danshen, inhibits the release of glutamate in rat cerebrocortical nerve terminals.Lin T Y, et al, journal of ethanol, 2013,147 (2): 488-496), ligustrazine (Tetramethylpyrazine reduces epileptogenesis progression in electrical kindling models by modulating hippocampal excitatory biotranssmission. Jin Y, et al, chemical Neuroscience,2019,10 (12): 4854-4863), gastrodin (Gastrodin reduces the severity ofstatus epilepticus in the rat pilocarpine model oftemporal lobe epilepsy by inhibiting Nav1.6 sodium cultures. Shah, et al, neuroscience, 2017,42 (2): 360-374), etc.; 2. antioxidant stress species such as baicalin (Hu Yungang. Influence of baicalin on the expression of hippocampal tissue HO-1 and NQO1 of mice induced by sea acid. Fuzhou: J.Fujian medical university, university of medical science, paper 2015), salidroside (Salidroside shows anticonvulsant and neuroprotective effects by activating the Nrf-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 rates. Liu D H, et al. Neurochemical Research,2019,44 (11): 2556-2565.), emodin (protection of emodin against hippocampal nerve cells of mice induced by sea acid. Ouyang Longjiang et al. International journal of neurological neuroscience, 2018,45 (5): 471-476.), glycyrrhizic acid (Glycyrrhizic acid protectsjuvenile epileptic rats against hippocampal damage through activation of Sirtune 3.Wu G, et al. Brain Research Bulletin,2020, 164:98-106), taurine (Taurine protects from pentylenetetrazole-induced behavioral and neurochemical changes in Zebrish. Fontica B D, et al. Focus. 5940, 5945 (5945): 3-583 et al); 3. protecting neuronal cells, such as hyperin (Hyperoside alleviates epilepsy-induced neuronal damage by enhancing antioxidant levels and reducing autophagy. Cao J, et al, ethophagospecol, 2020, 257:112884), ethanol extract of scorpions (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-pilocarpin. LiangY, et al, neurol Regeneration Research,2012,7 (6): 426-433), and the like; 4. inhibiting neuronal apoptosis, such as Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf/ARE signaling. Shi Y, et al Cellular Physiology and Biochemistry,2018,45 (1): 212-225,) puerarin (Puerarin research progress. Wang Donggong et al, western traditional Chinese medicine, 2017, 30 (1): 139-142), ostomin (ostomin effect on sea acid induced epilepsy rat neuronal Caspase-3 and Caspase-9 protein expression. Xie Hongting et al, traditional Chinese medicine information, 2015, 32 (2): 16-18), grassleaf sweelflag essential oil (grassleaf sweelflag rhizome essential oil anticonvulsant effect on epileptic rat PKC expression. Wang Kunfang et al. Traditional Chinese medicine pharmacology and clinic, 2015, 31 (1): 97-100), and the like.
The traditional Chinese medicine monomer compound provides a new idea for exploring a treatment scheme of epilepsy.
Disclosure of Invention
It is an object of the present invention to provide a compound which is a tanshinone IIA analogue with improved epileptic therapeutic effect.
In one aspect of the invention, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate thereof:
wherein:
x is selected from CR 0 、N；
R 0 Represents H, (C1-6) alkyl, (C1-6) alkoxy.
R 1 、R 2 Each independently selected from H, optionally substituted (C1-6) alkyl, optionally substituted (C1-6) alkoxy.
In one embodiment, X is selected from CH.
In one embodiment, X is selected from N.
In one embodiment, the optionally substituted means substituted or unsubstituted with one or more selected from the group consisting of: halogen, hydroxy, amino.
In one embodiment, R 1 、R 2 Each independently selected from H, (C1-4) alkyl.
Preferably, R 1 Selected from H.
Preferably, R 2 Selected from methyl and ethyl.
In one embodiment, the compound is selected from:
in the present invention, halogen means fluorine, chlorine, bromine or iodine.
In the present invention, alkyl means a straight-chain or branched saturated hydrocarbon group preferably having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
In one embodiment, a pharmaceutically acceptable salt of a compound of the invention refers to a pharmaceutically acceptable acid addition salt comprising: hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, malonate, succinate, tartrate, citrate, oxalate, methanesulfonate, p-toluenesulfonate, and the like, but are not limited thereto.
In the present invention, a solvate of a compound of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
In another aspect of the invention, the invention provides a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt, solvate thereof.
In one embodiment, the pharmaceutical compositions of the present invention may comprise one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions of the invention may be administered in standard manner for the condition to be treated, for example by topical, oral, rectal or parenteral administration. To achieve the above objects, the compounds of the present invention may be formulated in a manner known in the art into, for example, an aerosol, a dry powder formulation, a tablet, a capsule, a syrup, a powder, a granule, a water or oil solution or suspension, an emulsion, a dispersible powder, a suppository, an ointment, a cream, drops, and a sterile injectable water or oil solution or suspension.
Depending on the mode of administration, the pharmaceutical composition may contain 0.05-99wt%, e.g. 0.05-80wt%, e.g. 0.10-70wt%, e.g. 0.10-50wt% active ingredient, all weight percentages being calculated on the whole composition. Suitable pharmaceutical compositions of the invention are suitable for oral administration in unit dosage form, e.g. in the form of tablets or capsules, each containing 0.1mg to 0.2g of active ingredient.
The present invention provides a process for preparing the composition, which comprises mixing the active ingredient with a carrier.
The effective dosage of the compounds of the present invention can be determined according to age, weight, sex, method of administration, health condition and severity of the condition. For example, a dose of 0.1-1000 mg/day, preferably 1-500 mg/day, for an adult human weighing 70 kg. Such administration may be performed at a time up to several times a day, according to the discretion of a physician or pharmacist.
In another aspect of the invention, the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate thereof in the manufacture of a medicament for the prevention or treatment of epilepsy.
In another aspect of the invention, the present invention also provides a process for preparing a compound of formula I comprising the steps of:
converting the raw material a into an intermediate b containing boric acid ester or boric acid, and then carrying out coupling reaction with the raw material c to obtain an intermediate d; intermediate d is cyclized to form a compound of formula I;
wherein R is 1 -R 2 X is 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 the group consisting of
Advantageous effects
The invention provides a medicament for treating seizure disorders. The invention designs and synthesizes tanshinone IIA analogues by taking tanshinone IIA as a lead compound. The compound has the effects of inhibiting epilepsy, reducing incidence times and duration, and can reduce the level of homocysteine in a human body and reduce the damage of nerve functions. In addition, the effect of the compound in treating epilepsy is obviously better than that of tanshinone IIA, and the lead compound is surpassed.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
The experimental methods in the following examples are conventional methods unless otherwise specified. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications.
Example 1:
synthesis of intermediate 1-b: under the protection of nitrogen, 1-a (4.76 g,20 mmol) and B are added 2 Pin2(6.09g，24mmol)、K 2 CO 3 (5.53 g,40 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (0.29 g,0.4 mmol) was added to 1,4 dioxane (50 mL) and the reaction system was heated under reflux with stirring for 4h. 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, concentrated by distillation under reduced pressure, and the crude product was recrystallized from 95% ethanol, and dried to give intermediate 1-b (4.67 g, yield 82%); ESI-MS:286.22[ M+H ]] + 。
Synthesis of intermediate 1-d: under the protection of nitrogen, 1-b (2.85 g,10 mmol), 1-c (2.09 g,12 mmol) and K are added 2 CO 3 (2.77g，20mmol)、Pd(PPh 3 ) 4 (0.23 g,0.2 mmol) was added to 100mL of toluene/ethanol/water (2:1:1) mixed solvent and the above reactant system was heated at reflux for 5h. After the reaction is finished, naturally cooling to room temperature, adding distillationWater (100 mL), extraction with dichloromethane (150 mL x 2), drying of the combined organic layers over anhydrous magnesium sulfate, filtration, concentration of the filtrate by distillation under reduced pressure, and isolation of the crude product by column chromatography (silica gel, mobile phase petroleum ether: ethyl acetate=10:1), drying to give intermediate 1d (2.32 g, 78%); ESI-MS:298.24[ M+H ]] + 。
Synthesis of Compound 1: intermediate 1d (1.49 g,5 mmol) was dissolved in dry dichloromethane (50 mL) under nitrogen and cooled to-78deg.C, after which BBr was added dropwise 3 (1.0M in dichloromethane, 10 mmol). The reaction system was brought to 0 ℃, stirred for 1.5h, and water (50 mL) was carefully added. The reaction system was then stirred at room temperature for 1h and extracted with dichloromethane (50 mL. Times.3). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated by distillation under reduced pressure, and the crude product was purified by column chromatography (silica gel, mobile phase petroleum ether: ethyl acetate=30:1-5:1), dried to give compound 1 (1.16 g, 92%). ESI-MS:252.11[ M+H ]] + The method comprises the steps of carrying out a first treatment on the surface of the Elemental analysis: theoretical values, C,71.71; h,3.61; n,5.58; o,19.10; measured value C 15 H 9 NO 3 ，C,71.67；H,3.65；N,5.54；O,19.12。 1 H NMR(400MHz,CDCl 3 )δ8.90(d,J＝7.8Hz,1H),8.84(d,J＝7.8,Hz,1H),8.03(d,J＝7.8Hz,1H),7.89(d,J＝7.9Hz,1H),7.48(5,J＝7.8Hz,1H),6.91(s,1H),2.46(s,3H)。
Example 2:
synthesis of intermediate 2-b: 2-a (3.89 g,20 mmol), B under nitrogen 2 Pin2(6.09g，24mmol)、K 2 CO 3 (5.53 g,40 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (0.29 g,0.4 mmol) was added to 1,4 dioxane (50 mL) and the reaction system was heated under reflux with stirring for 5h. 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 pressureRecrystallizing the crude product with 95% ethanol, and drying to obtain intermediate 2-b (4.52 g, yield 79%); ESI-MS:287.17[ M+H ]] + 。
Synthesis of intermediate 2-d: under the protection of nitrogen, 2-b (2.86 g,10 mmol), 1-c (2.09 g,12 mmol) and K are added 2 CO 3 (2.77g，20mmol)、Pd(PPh 3 ) 4 (0.23 g,0.2 mmol) was added to 100mL of toluene/ethanol/water (2:1:1) mixed solvent and the above reactant system was heated at reflux for 7h. After the reaction was completed, naturally cooled to room temperature, distilled water (100 mL) was added, extracted with dichloromethane (150 ml×2), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated by distillation under reduced pressure, and the crude product was purified by column chromatography (silica gel, mobile phase petroleum ether: methanol=10:1), dried to give intermediate 1d (2.20 g, 74%); ESI-MS:299.12[ M+H ]] + 。
Synthesis of Compound 2: intermediate 2d (1.49 g,5 mmol) was dissolved in dry dichloromethane (50 mL) under nitrogen and cooled to-78deg.C, after which BBr was added dropwise 3 (1.0M in dichloromethane, 10 mmol). The reaction system was brought to 0 ℃, stirred for 2h, and water (50 mL) was carefully added. The reaction system was then stirred at room temperature for 1h and extracted with dichloromethane (50 mL. Times.3). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated by distillation under reduced pressure, and the crude product was purified by column chromatography (silica gel, mobile phase petroleum ether: ethyl acetate=15:1-3:1), dried to give compound 2 (1.13 g, 90%). ESI-MS:253.26[ M+H ]] + The method comprises the steps of carrying out a first treatment on the surface of the Elemental analysis: theoretical value C 14 H 8 N 2 O 3 C,66.67; h,3.20; n,11.11; o,19.03; actual measurement, C,66.63; h,3.22; n,11.14; o,19.00. 1 H NMR(400MHz,CDCl 3 )δ9.24(d,J＝7.8Hz,1H),8.62(d,J＝7.8Hz,1H),8.06(d,J＝7.9Hz,1H),7.95(d,J＝7.9Hz,1H),6.93(s,1H),2.46(s,3H)。
Test example:
1. material
Healthy male SD rats are selected for 48 animals, 10 weeks old and the mass is 200-250 g. All rats were kept under identical conditions and were placed in the same laboratory 1 week prior to the experiment, free movement and feeding water. Test drugs were prepared as in examples 1 and 2, with tanshinone IIA as a control. Rat homocysteine ELISA kit was purchased from Shanghai Biotechnology Co.
2. Method of
40 SD rats raised freely were intraperitoneally injected with lithium chloride (127 mg/kg) and after 24 hours, further intraperitoneally injected with pentyltoreq (35 mg/kg). After injection of pentylton for half an hour, rats were observed for symptoms such as chewing nodding, facial tic, clonus of extremities, and falling. Rating scale rating with Racine, 5 altogether: stage I: facial clonic system; stage II: rhythmic nodding; class III: unilateral anterior limb twitching; v level: twitching of the double forelimbs; v level: symptoms such as convulsion of limbs, loss of balance, jump and fall. Status epilepticus can be diagnosed if seizures of grade IV and grade V occur and last for half an hour. In the modeling process of rats, if IV-V level performance continuously appears, the modeling success is indicated, 35 rats which are finally modeled successfully and survive are obtained, 32 rats are randomly divided into 4 groups including a model group, a compound 1, a compound 2 and a tanshinone IIA group, wherein the compound 1, the compound 2 and the tanshinone IIA group are respectively subjected to gastric lavage for 40 mg/kg.d of medicine. Another 8 non-modeled rats were taken as a normal group, and normal and model group rats were perfused with an equal volume of physiological saline (10 mL/kg). 1 time/d, 14d of continuous administration.
3. Test of learning and memory ability
A Mois water maze (Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizuresin rats with kainite induced epiepsy. Grabenstatter H L, et al, epiepsia, 2010,46 (1): 8-14) is used, 4 different mark points are arranged on the wall of a circular pool (water temperature 26.5+/-0.8 ℃) with the height of 0.5m, the diameter of 1.25m and the water depth of 0.3m, a dark platform with the diameter of 9cm and the height of 28cm is arranged in the center of the pool, and the top of the platform is positioned at 1.5cm below the water surface. The water maze external reference remained unchanged during the training test. Training time is 5 days, rats are placed into the pool by taking 4 mark points as water inlet points respectively, and the time period for the rats to swim to the platform is recorded. If the rat does not find the platform within 120 seconds, it is manually introduced to the platform and latency is recorded as 120 seconds. All rats were kept for a maximum of 30 seconds after being placed on the bench and then placed into water from different marker points for detection. The test was performed for 4 days continuously, the platform in water was removed at 5 days, rats were placed in water from the pool wall, and the number of times the rats traversed the original platform position in 60 seconds was recorded.
4. Seizure condition
The epileptic rats of the model group and the administration group were observed separately, the frequency of epileptic seizures of the rats, the duration of each seizure was recorded, and the group-to-group comparison was performed.
5. Detection of homocysteine level in rat hippocampal tissue
Hippocampal tissue of 1cm×1cm in size was taken from rats and stored in a refrigerator at-50 ℃. Taking out before use, centrifuging to obtain supernatant, and comparing the homocysteine level by high performance liquid chromatography according to the operation steps on ELISA kit instruction.
6. Analysis of results
Statistical treatment was performed using SPSS22.0 statistical software. The mean ± standard deviation (-x ± s) is used to represent the metrology data, the F test is used to represent the comparison between groups, the test level is α=0.05, and p <0.05 is statistically significant.
a. Overall situation
The seizure stage of the epileptic model rat is manifested by increased excitability, fast respiration, white foam of mouth, unstable standing and convulsion of limbs.
b. Spatial learning memory capability
As can be seen from the results in table 1, the model group rats escape latency period is significantly longer than that of the normal group, and the number of channel penetrating times is significantly less than that of the normal group, which indicates that the modeling is successful. The escape latency time of the rats in the group 1 and the group 2 is obviously shorter than that of the model group and the tanshinone IIA group, and the number of times of passing through the platform is more than that of the model group and the tanshinone IIA group, which proves that the group 1 and the group 2 have obvious effects on improving the space learning and memory capacity of the epileptic rats and are superior to that of the tanshinone IIA group.
Table 1: spatial learning and memory capacity comparison
Note that: in contrast to the normal group, * P＜0.05， ** P＜0.01， *** p is less than 0.001; in contrast to the set of models, # P＜0.05， ## P＜0.01， ### p is less than 0.001; compared with the tanshinone IIA group, & P＜0.05， && P＜0.01
c. seizure condition comparison
As can be seen from the results of table 2, the seizure duration and seizure frequency of the rats in the compound 1 group and the compound 2 group were significantly lower than those of the model group and lower than those of the tanshinone IIA group, which indicates that the compound 1 group and the compound 2 group had a significant effect in improving the epileptic condition of the epileptic rats and were superior to those of the tanshinone IIA group.
Table 2: seizure condition comparison
Note that: in contrast to the set of models, ## P＜0.01， ### p is less than 0.01; compared with the tanshinone IIA group, && P＜0.01
d. comparison of homocysteine levels
Homocysteine is a sulfur-containing amino acid, is an intermediate metabolite of methionine, and belongs to excitatory amino acids. Homocysteine as an excitatory neurotransmitter further induces seizures and adds to the symptoms of seizures by stimulating brain endothelial cell neurotransmission and increasing endothelial cell membrane permeance. From the results in Table 3, it can be seen that the homocysteine level of the normal group of rats is lower, but the model group of rats is significantly increased, while the compounds 1 and 2 have the effect of reducing homocysteine level, and are significantly better than the tanshinone IIA group.
Table 3: comparison of homocysteine levels
Note that: in contrast to the normal group, *** p is less than 0.001; compared with the model group; # P＜0.05， ## p is less than 0.01; compared with the tanshinone IIA group, & P＜0.05
in general, the compounds of the present invention have the effects of inhibiting epilepsy, reducing the number of incidences, reducing duration, and reducing homocysteine levels in the body, and reducing the impairment of neurological function.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and additions may be made to those skilled in the art without departing from the method of the present invention, which modifications and additions are also to be considered as within the scope of the present invention.

Claims (9)

1. A compound of formula I or a pharmaceutically acceptable salt, solvate thereof:
wherein:
x is selected from CR 0 、N；
R 0 Represents H, (C1-6) alkyl, (C1-6) alkoxy.
R 1 、R 2 Each independently selected from H, optionally substituted (C1-6) alkyl, optionally substituted (C1-6) alkoxy.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, wherein X is selected from CH, N.
3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, wherein said optionally substituted means substituted or unsubstituted with one or more selected from the group consisting of: halogen, hydroxy, amino.
4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, wherein R 1 、R 2 Each independently selected from H, (C1-4) alkyl.
5. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, wherein R 1 Selected from H; r is R 2 Selected from methyl and ethyl.
6. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, wherein the compound is selected from:
7. a pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1-6 or a pharmaceutically acceptable salt, solvate thereof.
8. Use of a compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for the prevention or treatment of epilepsy.
9. A process for preparing a compound of formula I as described in claim 1, comprising the steps of:
converting the raw material a into an intermediate b containing boric acid ester or boric acid, and then carrying out coupling reaction with the raw material c to obtain an intermediate d; intermediate d is cyclized to form a compound of formula I;
wherein R is 1 -R 2 X is as rightAs described in claim 1, xa, xb are each independently selected from chlorine or bromine, ra, rb are each independently selected from (C1-4) alkyl, R B Selected from the group consisting of
CN202310950772.0A 2023-07-31 2023-07-31 Medicine for treating epileptic seizure disease and preparation method thereof Pending CN116987091A (en)

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