CN113651767B - Benzisoxazole heterocyclic compound and preparation method and application thereof - Google Patents
Benzisoxazole heterocyclic compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a benzisoxazole heterocyclic compound, a preparation method and application thereof, and the structural formula of the benzisoxazole heterocyclic compound comprises the formulas (I), (II) and (III), and particularly provides a specific preparation method of the benzisoxazole heterocyclic compound. The derivatives have better anticonvulsant activity and can be used as antiepileptic drugs.
Description
Technical Field
The invention belongs to the fields of organic synthesis and medicinal chemistry, and particularly relates to a benzisoxazole heterocyclic compound, and a preparation method and application thereof.
Background content
Epilepsy is a group of chronic brain diseases characterized by transient central nervous system dysfunction caused by abnormal discharge of brain neurons, and has the characteristics of sudden and repeated attacks. Various antiepileptic drugs such as phenobarbital, carbamazepine, phenytoin sodium, valproic acid have been used in clinical applications. Although these drugs are capable of protecting patients from various epileptic convulsions to varying degrees, they have side effects and tolerability, preventing their use in long-term therapy. In order to improve the therapeutic effect and eliminate or reduce side effects, new compounds with new structural features and new mechanisms of action are needed.
Disclosure of Invention
The invention aims to solve the problems, and provides the benzisoxazole heterocyclic compound which has low toxicity and can treat epilepsy, and the synthesis method of the compound is simple and reasonable and has low production cost.
The invention is realized by the following technical scheme: a benzisoxazole heterocyclic compound, which has the structural general formula (I), (II) and (III):
wherein R1 represents one of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-12 membered aromatic heterocycle containing N, O atoms and a substituted or unsubstituted 5-13 membered saturated heterocycle containing N, O atoms;
r2 represents a substituted or unsubstituted 5-13 membered saturated heterocyclic ring containing a secondary amino N atom;
r3 is one of substituted or unsubstituted thiazolidine-2, 4-dione, thiothiazolidine-4-ketone, imidazoline-2, 4-dione, 2,4, 6-pyrimidine trione, 2-thiobarbituric acid group and indole-2-ketone.
Further, one or more hydrogen atoms on the substituted group in R1 are substituted with one or more of the following groups: halogen, deuterium atom, cyano, hydroxy, amino, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 sulfonyl.
One or more hydrogen atoms on the substituted group in R2 are substituted with one or more of the following groups: carbonyl, halogen, deuterium atom, cyano, hydroxy, amino, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 sulfonyl.
The invention also provides a preparation method of the compound, and the structural general formula of the used starting materials is as follows (IV), (V) and (VI):
Further, the compound of formula (I) is prepared by condensation reaction of equimolar starting material formula (IV) and ammonia compound in organic solvent, wherein the ammonia compound is one of substituted or unsubstituted aniline, substituted or unsubstituted 5-12 membered aromatic heterocyclic primary ammonia containing N, O atoms and substituted or unsubstituted 5-13 membered saturated heterocyclic primary ammonia containing N, O atoms, the organic solvent is DCM, DMF or DMSO, and the condensation reaction is SOCl 2 Acid chloride process.
Further, the compound of the formula (II) is prepared by reacting equimolar starting material formula (V) with one of substituted or unsubstituted pyrrolidine-2, 5-dione, pyrrolidine-2-ketone, 3, 4-dihydroquinoline-2 (1H) -ketone, thiazolidine-2, 4-dione, thiothiazolidine-4-ketone, imidazoline-2, 4-dione, indole-2-ketone, 2,4, 6-pyrimidine trione, 2-thiobarbituric acid and piperidine under the conditions of organic solvent, alkaline environment, heating and catalyst;
the organic solvent is acetonitrile or DMF, and the alkaline condition is K 2 CO 3 Or NaH.
Further, the compound of formula (III) is prepared by reflux reaction of equimolar starting material formula (VI) and one of substituted or unsubstituted thiazolidine-2, 4-dione, 2-thiothiazolidine-4-one, imidazoline-2, 4-dione, 2,4, 6-pyrimidine trione group and 2-thiobarbituric acid group in an acetic acid/sodium acetate system or reflux reaction of indole-2-ketone group in a piperidine/ethanol system.
Further, the preparation method of the compound of the formula (IV) as the starting material comprises the following steps: mixing sodium hydroxide, hydroxylamine hydrochloride and ethanol, stirring uniformly, adding 4-hydroxycoumarin into the mixture, heating and stirring the mixture at 75-85 ℃ for reaction for 12-18 hours, recovering ethanol under reduced pressure after the reaction is finished, dissolving residues in sodium bicarbonate aqueous solution, filtering, adjusting the pH value of the filtrate to be 3-5 by using hydrochloric acid solution, filtering, washing a filter cake to be neutral by using water, and drying the filter cake in a vacuum drying oven to obtain a compound of a starting material formula (IV), wherein the molar ratio of the sodium hydroxide to the hydroxylamine hydrochloride to the 4-hydroxycoumarin is 1:1: (0.7-0.8).
The preparation method of the starting material compound of formula (V) comprises the following steps: reacting a starting material compound of formula (IV) with a halogenating reagent in an organic solvent for 4-8h, and heating the obtained product in 20% sulfuric acid to remove carboxylic acid to obtain a starting material compound of formula (V), wherein the molar ratio of the compound of formula (IV) to the halogenating reagent is 1: (1-1.2) the organic solvent is glacial acetic acid, CCl 4 、 CHCl 3 DCM, dioxane or DMF, the halogenating reagent being Br 2 HBr, HCl or thionyl chloride.
The preparation method of the starting material compound of formula (VI) comprises the following steps: dissolving a starting material compound shown as a formula (V) and sodium metal in absolute ethyl alcohol, stirring and carrying out reflux reaction, dissolving the obtained initial product in an organic solvent, then cooling to-78 ℃ under the protection of argon, stirring, and carrying out BBr 3 Adding an organic solvent into the reaction solution, stirring and reacting at the temperature of-78 ℃, dissolving the obtained product into the organic solvent, then adding an oxidant, and stirring and reacting at the room temperature to obtain a starting material compound shown as a formula (VI), wherein the molar ratio of the compound shown as a formula (V) to the metal sodium is 1: (0.4-0.5), primary product, BBr 3 The molar ratio of the organic solvent is 1:2, and the organic solvent is DCM or CHCl 3 The oxidant is pyridine dichromate, KMnO 4 、K 2 Cr 2 O 7 、KClO 3 Concentrated H 2 SO 4 、HNO 3 、MnO 2 Or H 2 O 2 。
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an enantiomer, diastereomer, racemate or mixture thereof of the above benzisoxazole heterocyclic compound, and one or more pharmaceutically acceptable carrier materials and/or adjuvants.
The invention also provides application of the benzisoxazole heterocyclic compound or the pharmaceutical composition in treating mental system diseases.
Further, the mental system disease is epilepsy, and the epilepsy comprises epileptic grand mal seizure, epileptic small seizure, primary epilepsy and secondary epilepsy.
The pharmaceutically acceptable carrier is selected from the following groups: lactose, sucrose, dextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, cellulose lower alkyl ether corn starch, potato starch, gum, syrup, peanut oil, olive oil, phospholipids, glycerol monostearate, glycerol distearate, fatty acids, fatty acid amines, colorants, preservatives, flavoring agents, water, ethanol, propanol, physiological saline, dextrose solution, or combinations thereof.
The pharmaceutically acceptable auxiliary materials are selected from the following groups: binders, fillers, diluents, disintegrants, suspending agents, slow (controlled) release agents, lyoprotectants, coating agents, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, osmotic pressure modifiers, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, lipid-soluble matrices, oleaginous matrices, porogens, gelling agents, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.
The dosage of the compounds of the present invention to achieve the desired therapeutic effect will depend on a number of factors, such as the particular compound selected, the intended use, the mode of administration and the clinical condition of the patient. Daily doses typically range from 0.3mg to 100mg (typically 3mg to 50 mg) per day per kilogram of body weight, intravenous doses range from 0.3mg to 1.0mg, which are suitable for administration in the form of an infusion of 10ng to 100 ng/kg/minute. Suitable infusion solutions for this purpose may contain, for example, from 0.ng to 100mg, typically from lgg to 100mg, per ml. A single dose may contain, for example, lmg to 10g of active ingredient. Thus, a single dose formulation such as a tablet or capsule which contains, for example, lmg to 100mg for injection and which can be orally administered may contain, for example, lmg to 1000mg, typically 10 to 600mg. For the prophylaxis and/or treatment of the abovementioned disorders, the compounds of the formula I can be used as medicaments per se, but they are preferably in the form of pharmaceutical compositions with compatible carriers.
Drawings
FIG. 1 is Na of Compound Z-6b V 1.1 State dependency (TP 1) blocking study plots for channels;
FIG. 2 is Na of Compound Z-6b V 1.1 usage dependency of channel (TP 2) blocking study;
FIG. 3 is Na of Compound Z-6b V 1.2 status dependence of channels (TP 1) blocking study;
FIG. 4 is Na of Compound Z-6b V 1.2 usage dependency of channel (TP 2) blocking study plots;
FIG. 5 is Na of Compound Z-6b V 1.3 State dependency (TP 1) blocking study plots of channels;
FIG. 6 is Na of Compound Z-6b V 1.3 usage dependency (TP 2) blocking study plots;
FIG. 7 is Na of Compound Z-6b V 1.6 status dependence of channel (TP 1) blocking study;
FIG. 8 is Na of Compound Z-6b V 1.6 usage dependency (TP 2) blocking study plots.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
1. Preparation of the inventive Compounds of formula (I)
Examples 1-5 provide a benzisoxazole heterocyclic compound, and the structural general formula of the compound is shown as formula (I):
example 1
This example provides a benzisoxazole heterocyclic compound named 2- (benzo [ d ] isoxazol-3-yl) -N-phenylacetamide (Z-2 a) prepared by:
(1) Preparation of starting Material Compound (Z-1) of formula (IV):
a mixture of sodium hydroxide (5.6 g,0.14mo 1), hydroxylamine hydrochloride (6.95 g,0.14mo 1) and ethanol (120 ml) was stirred for 10min, and 4-hydroxycoumarin (16.2 g,0.1mo 1) was added thereto, and the reaction was heated and stirred at 80℃for 16h. After the reaction was completed, ethanol was recovered under reduced pressure, the residue was dissolved in 80 mL of 10% sodium bicarbonate and filtered, the filtrate was adjusted to ph=4 with 6 mol/L hydrochloric acid solution, the solid was precipitated, filtered, the filter cake was washed to neutrality with water, and dried in a vacuum oven to obtain 31.2 g as a white solid Z-1 in 75% yield, i.e., the starting material compound of formula (IV). mp:127-129 ℃; 1 H-NMR (DMSO-d6, 600 MHz): d12.93 (s, 1H, br, COOH), 7.86 (d, 1H, J = 7.8 Hz, ArH), 7.74 (d, 1H, J = 8.4 Hz, ArH), 7.65-7.67 (m, 1H, ArH), 7.39-7.42 (m, 1H, ArH), 4.11 (s, 2H, CH2). 13 C-NMR (CDCl3, 151 MHz,): d173.89, 163.35, 151.94, 130.22, 123.83, 121.63, 121.09, 110.07, 31.28. ESI-HRMS calcd for C 9 H 7 NO 3 ([M+H]+): 178.0426; found: 178.0499。
(2) Preparation of 2- (benzo [ d ] isoxazol-3-yl) -N-phenylacetamide (Z-2 a):
z-1 (278 mg,1.57 mmol) was dissolved in anhydrous DCM (20 mL) and SOCl was added under ice-bath conditions 2 (2.50 mmol) the reaction was stirred at 40℃for 3h, after completion of the reaction (monitored by TLC), the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3' -30 mL), the organic phases were separated and combined, taken up in Na 2 SO 4 Drying, evaporating the solvent, and mixing the obtained product with dry DCM and dry Et 3 N（10 equivalent) and aniline (1.0 equivalent) was added dropwise under ice bath conditions, and after stirring at room temperature for 6 hours, water was added to the reaction solution for extraction, and the organic layer was combined and dried over anhydrous Na 2 SO 4 After drying, spin drying, purifying the final product by column chromatography to obtain white solid Z-2a (yield 42%); mp 131-132 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d8.18 (s, 1H, br, NH), 7.86 (d, 1H, J = 7.8 Hz, ArH), 7.63-7.64 (m, 2H, ArH), 7.52 (dd, 2H, J = 7.8 Hz, ArH), 7.38-7.41 (m, 1H, ArH), 7.33 (t, 2H, J = 7.8 Hz, ArH), 7.13 (t, 1H, J = 7.8 Hz, ArH), 4.17 (s, 2H, CH 2 ). ESI-HRMS calcd for C 15 H 12 N 2 O 2 ([M+H]+): 253.0899; found: 253. 0976。
the structural formula is as follows:
example 2
This example provides a benzisoxazole heterocyclic compound named 2- (benzo [ d ] isoxazol-3-yl) -N- (2-fluorophenyl) acetamide (Z-2 b) which is prepared by the following method:
(1) Preparation of starting Material Compound (Z-1) of formula (IV):
a mixture of sodium hydroxide (5.6 g,0.14mo 1), hydroxylamine hydrochloride (6.95 g,0.14mo 1) and ethanol (120 ml) was stirred for 10min, and 4-hydroxycoumarin (15.9 g,0.098mo 1) was added thereto, and the reaction was heated and stirred at 75℃for 12h. After the reaction is completed, ethanol is recovered under reduced pressure, the residue is dissolved in 80 mL of 10% sodium bicarbonate and filtered, the filtrate is adjusted to ph=3 with 6 mol/L hydrochloric acid solution, the solid is precipitated, filtered, the filter cake is washed to neutrality with water, and dried in a vacuum drying oven to obtain white solid Z-1, namely the starting material compound of formula (IV).
(2) Preparation of 2- (benzo [ d ] isoxazol-3-yl) -N- (2-fluorophenyl) acetamide (Z-2 b):
reference is made to the synthesis of example 1, which is identical to that of example 1The difference is that the organic solvent in this example is DMF and the ammonia compound is 2-fluoroaniline, so as to obtain white solid Z-2b (yield 40%); mp, 140-141 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d8.32 (s, 1H, br, NH), 8.27 (t, 1H, J = 7.8 Hz, ArH), 7.84 (d, 1H, J = 7.8 Hz, ArH), 7.61-7.65 (m, 2H, ArH), 7.38-7.40 (m, 1H, ArH), 7.12-7.15 (m, 1H, ArH), 7.06-7.10 (m, 2H, ArH), 4.21 (s, 2H, CH 2 ). ESI-HRMS calcd for C 15 H 11 FN 2 O 2 ([M+H]+): 271.0805; found: 271.0879。
the structural formula is as follows:
example 3
This example provides a benzisoxazole heterocyclic compound named 2- (benzo [ d ] isoxazol-3-yl) -N- (3-chlorophenyl) acetamide (Z-2 c) which is prepared by the following method:
(1) Preparation of starting Material Compound (Z-1) of formula (IV):
a mixture of sodium hydroxide (5.6 g,0.14mo 1), hydroxylamine hydrochloride (6.95 g,0.14mo 1) and ethanol (120 ml) was stirred for 10min, and 4-hydroxycoumarin (18.1 g,0.112mo 1) was added thereto, and the reaction was heated and stirred at 85℃for 18h. After the reaction is completed, ethanol is recovered under reduced pressure, the residue is dissolved in 80 mL of 10% sodium bicarbonate and filtered, the filtrate is adjusted to ph=5 with 6 mol/L hydrochloric acid solution, the solid is precipitated, filtered, the filter cake is washed to neutrality with water, and dried in a vacuum drying oven to obtain white solid Z-1, namely the starting material compound of formula (IV).
(2) Preparation of 2- (benzo [ d ] isoxazol-3-yl) -N- (3-chlorophenyl) acetamide (Z-2 c):
the synthetic method of reference example 1 differs from example 1 in that the organic solvent in this example is DMSO and the ammonia compound is 3-chloroaniline, yielding a pale yellow solid Z-2c (yield 67%); mp 160-161 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d8.32 (s, 1H, br, NH), 7.84 (d, 1H, J = 7.8 Hz, ArH), 7.68 (t, 1H, J = 1.2 Hz, ArH), 7.62-7.65 (m, 2H, ArH), 7.39-7.42 (m, 1H, ArH), 7.36 (dd, 1H, J = 7.8, 1.2 Hz, ArH), 7.24 (t, 1H, J = 7.8 Hz, ArH), 7.11 (dd, 1H, J = 7.8, 1.2 Hz, ArH), 4.17 (s, 2H, CH 2 ). ESI-HRMS calcd for C 15 H 11 ClN 2 O 2 ([M+H]+): 287.0509; found: 287.0579。
the structural formula is as follows:
example 4
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ]]Isoxazol-3-yl) -N- (4- (tert-butyl) phenyl) acetamide (Z-2 d) was prepared by the method described in reference to example 1, which differs from example 1 in that the amino compound in this example was 4-tert-butylaniline, giving a light brown solid Z-2d (yield22%); mp, 102-104 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d8.06 (s, 1H, br, NH), 7.85 (d, 1H, J = 7.8 Hz, ArH), 7.60-7.64 (m, 2H, ArH), 7.42-7.44 (m, 1H, ArH), 7.37-7.40 (m, 1H, ArH), 7.32-7.35 (m, 1H, ArH), 4.16 (s, 2H, CH 2 ) , 1.30 (s, 9H, 3CH 3 )。
the structural formula is as follows:
example 5
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ]]Isoxazol-3-yl) -N- (2, 6-difluorophenyl) acetamide (Z-2 e) was prepared by the method described in reference to example 1, which differs from example 1 in that the ammonia compound in this example was 2, 6-dichloroaniline, giving white solid Z-2e (yield 53%); mp, 192-194 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d7.85 (d, 1H, J = 7.8 Hz, ArH), 7.73 (s, 1H, br, NH), 7.62-7.64 (m, 2H, ArH), 7.39-7.42 (m, 1H, ArH), 7.21-7.26 (m, 1H, ArH), 6.96 (t, 2H, J = 7.8 Hz, ArH), 4.24 (s, 2H, CH 2 ). ESI-HRMS calcd for C 15 H 10 F 2 N 2 O 2 ([M+H]+): 289.0710; found: 289.0784。
the structural formula is as follows:
2. preparation of the inventive Compound of formula (II)
Examples 6-9 provide benzisoxazole heterocyclic compounds with the structural general formula shown in formula (II):
the synthesis process of the compound of formula (II) is as follows:
example 6
The embodiment provides a benzisoxazole heterocyclic compound, which is named as 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidine-2, 5-dione (Z-6 a), and the preparation method comprises the following steps:
(1) A process for the preparation of the starting material compound (Z-5) of formula (V):
the above synthesized compound Z-1 (1.42.0 g,8.0 mmol) was dissolved in 5mL of glacial acetic acid, bromine (0.45 mL,8.8 mmol) was slowly added dropwise with stirring (dropwise addition time: 30 min), the reaction was 6. 6h at room temperature, and then the reaction solution was poured into ice water (20 mL), stirred, the solid was precipitated, filtered, and the filter cake was dried to give a pale yellow solid Z-4 (1.74 g, yield: 85%). Compound Z-4 (1.74 g,6.8 mmol) was dissolved in 20% sulfuric acid (6 mL) and returned with stirringStream 4h, then cooled to room temperature, filtered and distilled with water vapor, 1.28g of white crystals Z-5 are obtained as compound of formula (V) in 76% yield. mp 61-62 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d 7.84 (d, 1H, J = 7.8 Hz, ArH), 7.58-7.62 (m, 2H, ArH), 7.38-7.40 (m, 1H, ArH), 4.75 (s, 2H, CH 2 ). ESI-HRMS calcd for C 8 H 6 BrNO ([M+H]+): 211.9633; found: 211.9704。
(2) Preparation of 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidine-2, 5-dione (Z-6 a):
the synthesized compounds Z-5 (1.0 equivalent) and K are mixed 2 CO 3 (2.0 eq.) and catalytic equivalent KI were mixed uniformly, a mixed solution of DMF and pyrrolidine-2, 5-dione was added dropwise, and reacted overnight at 80℃after completion of the reaction (TLC monitoring), the reaction solution was poured into cold water, extracted with ethyl acetate, the organic layers were combined, and the mixture was taken up in anhydrous Na 2 SO 4 Drying, spin drying, and purifying the final product by column chromatography to obtain brown solid Z-6a (yield 67%); mp 181-183 ℃; 1 H-NMR (DMSO-d6, 600 MHz): d 7.89 (d, 1H, J = 7.8 Hz, ArH), 7.75 (d, 1H, J = 8.4 Hz, ArH), 7.67-7.69 (m, 1H, ArH), 7.43 (t, 1H, J = 7.8 Hz, ArH), 4.99 (s, 2H, CH 2 ), 2.74 (s, 4H, 2CH 2 ). ESI-HRMS calcd for C 12 H 10 N 2 O 3 ([M-H]+): 231.0691; found: 231.0764。
the structural formula is as follows:
。
example 7
This example provides a benzisoxazole-based heterocyclic compound, named 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidin-2-one (Z-6 b), which is prepared by:
(1) A process for the preparation of the starting material compound (Z-5) of formula (V):
the above synthesized compound Z-1 (1.42.0 g,8.0 mmol) was dissolved in 5ml Cl 4 Slowly drop wise with stirring, HBr (8.8mmol), 4h at room temperature, then the reaction solution was poured into ice water (20 ml), stirred, the solid precipitated, filtered, and the filter cake was dried to give a pale yellow solid Z-4. Compound Z-4 (1.74 g,6.8 mmol) was dissolved in 20% sulfuric acid (6 mL), refluxed with stirring for 4 hours, then cooled to room temperature, filtered and distilled with water vapor to obtain 1.28g of white crystals Z-5, i.e., the compound of formula (V).
(2) Preparation of 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidin-2-one (Z-6 b):
after the above-synthesized compound Z-5 (1.0 equivalent), naH (2.0 equivalent) and catalytic equivalent KI were mixed uniformly, a mixed solution of acetonitrile and pyrrolidin-2-one was added dropwise, and the reaction was carried out at 80℃overnight, after completion of the reaction (TLC monitoring), the reaction solution was poured into cold water, extracted with ethyl acetate, and the organic layers were combined with anhydrous Na 2 SO 4 Drying, spin drying, and purifying the final product by column chromatography to obtain colorless oily liquid Z-6b (yield 56%); 1 H-NMR (DMSO-d6, 600 MHz): d 7.82 (d, 1H, J = 7.8 Hz, ArH), 7.76 (d, 1H, J = 8.4 Hz, ArH), 7.67 (t, 1H, J = 7.8 Hz, ArH), 7.42 (t, 1H, J = 7.8 Hz, ArH), 4.81 (s, 2H, CH 2 ), 3.33 (t, 1H, J = 7.2 Hz, CH 2 ), 2.31 (t, 2H, J = 7.8 Hz, CH 2 ), 1.89-1.95 (m, 3H, CH 3 ). ESI-HRMS calcd for C 12 H 12 N 2 O 2 ([M+Na]+): 239.0796; found: 239.0794。
the structural formula is as follows:
。
example 8
This example provides a benzisoxazole heterocyclic compound named 3- (piperidin-1-ylmethyl) benzo [ d ] isoxazole (Z-6 c) which is prepared by:
(1) A process for the preparation of the starting material compound (Z-5) of formula (V):
the above synthesized compound Z-1 (1.42.0 g,8.0 mmol) was dissolved in 5mL of CM, bromine (0.45 mL,8.8 mmol) was slowly added dropwise with stirring, 8.8 h was reacted at room temperature, then the reaction solution was poured into ice water (20 ml), stirred, the solid was precipitated, filtered, and the cake was dried to obtain pale yellow solid Z-4. Compound Z-4 (1.74 g,6.8 mmol) was dissolved in 20% sulfuric acid (6 mL), refluxed with stirring for 4 hours, then cooled to room temperature, filtered and distilled with water vapor to obtain 1.28g of white crystals Z-5, i.e., the compound of formula (V).
(2) Preparation of 3- (piperidin-1-ylmethyl) benzo [ d ] isoxazole (Z-6 c):
after the above synthesized compound Z-5 (1.0 equivalent), naH (2.0 equivalent) and catalytic equivalent KI were mixed uniformly, a mixed solution of acetonitrile and piperidine was added dropwise, and the reaction was stirred at 60℃for 3 hours, after the completion of the reaction (TLC monitoring), the reaction solution was poured into cold water, extracted with ethyl acetate, the organic layers were combined, and the mixture was purified with anhydrous Na 2 SO 4 Drying, spin drying, and purifying the final product by column chromatography to obtain pale yellow solid Z-6c (yield 74%); mp 80-82 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d 7.97 (dt, 1H, J = 7.8, 1.2 Hz, ArH), 7.55-7.59 (m, 2H, ArH), 7.31-7.34 (m, 1H, ArH), 3.94 (s, 2H, CH 2 ), 2.54 (s, 4H, 2CH 2 ), 1.61-1.65 (m, 4H, 2CH 2 ), 1.42-1.51 (m, 2H, CH 2 ). ESI-HRMS calcd for C 13 H 16 N 2 O ([M+H]+): 217.1263; found: 217.1331。
the structural formula is as follows:
。
example 9
This example provides a benzisoxazole-based heterocyclic compound named 1- (benzo [ d ] isoxazol-3-ylmethyl) -3, 4-dihydroquinolin-2 (1H) -one (Z-6 d) prepared by:
(1) The process for the preparation of the starting material compound of formula (V) (Z-5), referred to example 1, differs from example 1 in that the organic solvent is DMF.
(2) 1- (benzo [ d)]Isoxazol-3-ylmethyl) -3, 4-dihydroquinoline-preparation of 2 (1H) -ketone (Z-6 d): the synthesized compounds Z-5 (1.0 equivalent) and K are mixed 2 CO 3 (2.0 eq.) and catalytic equivalent KI were mixed uniformly, a mixed solution of DMF and 3, 4-dihydroquinolin-2 (1H) -one was added dropwise, and reacted overnight at 80℃after completion of the reaction (TLC monitoring), the reaction solution was poured into cold water, extracted with ethyl acetate, the organic layers were combined, and the mixture was taken up in anhydrous Na 2 SO 4 Drying, spin drying, and purifying the final product by column chromatography to obtain a white solid Z-6d (yield 54%); mp 71-73 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d 7.86 (dt, 1H, J = 7.8, 1.2 Hz, ArH), 7.53-7.57 (m, 2H, ArH), 7.42 (d, 1H, J = 8.4 Hz, ArH), 7.29-7.32 (m, 1H, ArH), 7.24 (td, 1H, J = 7.8, 1.2 Hz, ArH), 7.15 (dd, 1H, J = 7.2, 0.6 Hz, ArH), 7.10 (td, 1H, J = 7.8, 1.2 Hz, ArH), 5.60 (s, 2H, CH 2 ), 2.96 (t, 2H, J = 7.8 Hz, CH 2 ), 2.80 (t, 2H, J = 7.8 Hz, CH 2 ). ESI-HRMS calcd for C 17 H 14 N 2 O 2 ([M+H]+): 279.1055; found: 279.1123。
the structural formula is as follows:
。
3. preparation of the inventive Compounds of formula (III)
Examples 10-13 provide benzisoxazole heterocyclic compounds having the structural general formula (III):
the synthesis process of the compound of formula (III) is as follows:
example 10
This example provides a benzisoxazole-based heterocyclic compound named 5- (benzo [ d ] isoxazol-3-ylmethylene) thiazolidine-2, 4-dione (Z-10 a) prepared by:
step one: the above synthesized compound Z-5 (800 mg,3.8 mmol) and sodium (4 g) were dissolved in absolute ethanol (6 ml) under ice bath conditions, stirred and refluxed for 1.5 h until no bubbles were formed in the reaction solution. The reaction solution was cooled to room temperature, filtered, and the ethanol solvent was removed by rotary evaporation to give 0.27, g as white crystalline product Z-7 in 40% yield. 1 H-NMR (CDCl 3 , 600 MHz): d7.86 (dt, 1H, J = 7.8, 1.2 Hz, ArH), 7.58-7.62 (m, 2H, ArH), 7.34-7.38 (m, 1H, ArH), 4.90 (s, 2H, CH 2 ), 3.47 (s, 2H, CH 3 )。
Step two: compound Z-7 (380 mg,2.1 mmol) was dissolved in DCM (3 mL) and then cooled to-78℃under argon and stirred for 30 min, BBr was taken up 3 (1.08 g,4.2 mmol) and DCM (3 mL) were added to the above reaction solution and stirred at-78℃for 30h. After completion of the reaction, the reaction was warmed to room temperature and filtered, and the solvent was removed by evaporation to obtain 0.28. 0.28 g crystal Z-8 in 88% yield. mp 71-73 ℃; 1 H-NMR (CDCl 3 , 600 MHz): d 7.86 (dt, 1H, J = 7.8, 1.2 Hz, ArH), 7.58-7.62 (m, 2H, ArH), 7.35-7.38 (m, 1H, ArH), 5.13 (s, 2H, CH 2 ); 13C NMR (151 MHz, CDCl 3 ) δ 163.28, 157.87, 130.20, 123.68, 121.92, 120.43, 109.89, 56.71。
step three: compound Z-8 (500 mg,3.3 mmol) was dissolved in DCM (50 mL), then pyridine dichromate (3.8 g,10 mmol) as an oxidant was added to the above solution and the reaction was stirred at room temperature for 3.5 h, then filtered, the solvent was removed by evaporation, and further purified by column chromatography using ethyl acetate and n-hexane as eluent to give 166 mg of product Z-9 in 34% yield. 1 H-NMR (CDCl 3 , 600 MHz): d10.46 (s, 1H, CHO), 8.23 (d, 1H, J = 7.8 Hz, ArH), 7.72 (d, 1H, J = 7.8 Hz, ArH), 7.68 (t, 1H, J = 7.8 Hz, ArH), 7.50 (d, 1H, J = 7.8 Hz, ArH)。
Step four: the above-synthesized was carried out in the presence of sodium acetate (2.24 g,0.4 mol) using acetic acid (7 mL) as a solventCompound Z-9 (0.07 mmol) was mixed with thiazolidine-2, 4-dione (0.07 mmol) and reacted under reflux with intermittent stirring 3h, with n-hexane and ethyl acetate as mobile phases in a 1:1 ratio, and the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was cooled to obtain a crystalline product, which was then filtered with a pump, washed with water, dried, and recrystallized from ethanol to form yellow solid Z-10a (yield 79%); mp 236 ℃; 1 H-NMR (DMSO-d6, 600 MHz): d12.79 (s, 1H, br, NH), 8.33 (d, 1H, J = 7.8 Hz, ArH), 8.16 (s, 1H, C=CH), 7.87 (d, 1H, J = 7.2 Hz, ArH), 7.74-7.77 (m, 1H, ArH), 7.52 (t, 1H, J = 7.2 Hz, ArH)。
the structural formula is as follows:
。
example 11
This example provides a benzisoxazole heterocyclic compound, which is named 5- (benzo [ d)]Isoxazol-3-ylmethylene) -2-thiothiazol-4-one (Z-10 b) was prepared according to the method of synthesis of example 10, which differs from example 10 in that: in this embodiment, the organic solvent in the second and third steps is CHCl 3 The oxidant in the third step is KMnO 4 In the fourth step, the compound Z-9 and the 2-thiothiazolidine-4-ketone are subjected to reflux reaction, and the reflux reaction time is 2 hours.
Finally obtaining yellow solid Z-10b (yield 90%); 1 H-NMR (DMSO-d6, 600 MHz): d13.99 (s, 1H, br, NH), 8.35 (d, 1H, J = 8.4 Hz, ArH), 8.30 (d, 1H, J = 2.4 Hz, C=CH), 7.88 (d, 1H, J = 8.4 Hz, ArH), 7.76 (t, 1H, J = 7.8 Hz, ArH), 7.53 (t, 1H, J = 7.8 Hz, ArH). ESI-HRMS calcd for C 11 H 6 N 2 O 2 S 2 ([M+H]+): 262.9871; found: 262.9945。
the structural formula is as follows:
。
example 12
This practice isEmbodiments provide a benzisoxazole-based heterocyclic compound, which is named 5- (benzo [ d)]Isoxazol-3-ylmethylene) imidazoline-2, 4-dione (Z-10 c) was prepared according to the method of example 10, which differs from example 10 in that: in this embodiment, the oxidant in step three is K 2 Cr 2 O 7 In the fourth step, the compound Z-9 and the imidazoline-2, 4-diketone are subjected to reflux reaction, and the reflux reaction time is 4 hours.
Finally obtaining yellow solid Z-10c (yield 20%); mp 255-257 ℃; 1 H-NMR (DMSO-d6, 600 MHz): d 11.53 (s, 1H, br, NH), 10.32 (s, 1H, br, NH), 8.20 (d, 1H, J = 7.8 Hz, ArH), 7.82 (d, 1H, J = 8.4 Hz, ArH), 7.70-7.73 (m, 1H, ArH), 7.47 (d, 1H, J = 7.8 Hz, ArH), 6.75 (s, 1H, ArH). ESI-HRMS calcd for C 11 H 7 N 3 O 3 ([M+H]+): 230.0487;found: 230.0564。
the structural formula is as follows:
。
example 13
This example provides a benzisoxazole heterocyclic compound, which is named as 3- (benzo [ d ] isoxazol-3-ylmethylene) indol-2-one (Z-10 d), and the preparation method refers to the synthesis method of example 10, and the difference from example 10 is that in this example, the specific steps of step four are as follows:
a mixture of the above synthesized compound Z-9 (61 mg,0.5 mmol), indol-2-one (61 mg,0.4 mmol), piperidine (26 mg,0.3 mmol) and ethanol (3 mL) was reacted in a reflux flask for 3h, then the reaction mixture was poured into water (10 mL) and acidified with acetic acid, and recrystallised from methanol to give a yellow solid Z-10d (yield56%); 1 H-NMR (DMSO-d6, 600 MHz): d10.82 (s, 1H, br, NH), 8.60 (d, 1H, J = 7.8 Hz, ArH), 8.19 (d, 1H, J = 7.8 Hz, ArH), 7.92 (d, 1H, J = 8.4 Hz, ArH), 7.78 (t, 1H, J = 7.8 Hz, ArH), 7.72 (s, 1H, ArH), 7.54 (t, 1H, J = 7.2 Hz, ArH), 7.38 (t, 1H, J = 7.8 Hz, ArH), 7.06 (t, 1H, J = 7.2 Hz, ArH), 6.94 (d, 1H, J = 7.8 Hz, ArH). ESI-HRMS calcd for C 16 H 10 N 2 O 2 ([M+H]+): 263.0742; found: 263.0815。
the structural formula is as follows:
。
4. use of the compounds of the invention for the treatment of epilepsy
The test animals in the experiments of the invention were male mice (Kunming mouse species, 20-25 g).
Screening of anticonvulsant Activity and neurotoxicity test of (one) Compounds
Referring to the "antiepileptic development program (Antiepileptic Drug Development Program) published by the national institutes of health (NIN), the anticonvulsant activity of compounds was evaluated using two models, the maximum electroconvulsive test (MES) and the pentatetrazole convulsive threshold test (scPTZ). Neurotoxicity screening was assessed using a rotarod method. The anticonvulsant activity and neurotoxicity screening results of the compounds are shown in table 1.
1. Maximum Electroconvulsive (MES) test
The MES test is a classical pharmacological model for evaluating the anticonvulsant activity of a compound, and if a compound is effective in the MES model, it is indicated that the compound has an antiepileptic seizure effect.
Experimental compounds: compounds Z-2a, Z-2b, Z-2c, Z-2d, Z-2e, Z-6a, Z-6b, Z-6c, Z-6d, Z-10a, Z-10b, Z-10c, Z-10d and Phenytoin (Phenytoin), phenobarbital (Phenobarbital), ethosuximide (Ethosuximide) prepared in examples 1-13.
The testing method comprises the following steps: mice were placed under temperature control (25-30 ℃) and fed for 24 hours during which time the mice were free to gain food and water to suit the environment, then pre-screened the mice the day prior to the formal experiment, and the mice were subjected to current on their ear electrodes for 0.3s during screening and used for the formal experiment. At 0.5h and 4 hours after administration of the test compound in the formal experiment, mice were energized with ear electrodes for 0.3s, and the appearance of hindlimb rigidity was considered convulsion, indicating that the test compound was ineffective. The absence of hindlimb rigidity was noted as anticonvulsant. The test subjects were formulated by dissolving the compounds in 50% aqueous polyethylene glycol. In the MES screen, the number of mice in each group was 3, and each compound was administered at 3 dose levels (30, 100, 300mg/kg body weight); the minimum active dose refers to the minimum dose at which 2-3 mice in the same subject mice dose group have no convulsions after administration.
Evaluation of results: most compounds showed some activity in MES experiments. The strongest active Z-6b showed very high seizure protection at a minimum dose of 30mg/kg for 0.5h, indicating the good properties of rapid onset of action of the compound at lower doses. At the same time, Z-6b was also active at higher doses of 100mg/kg at 4.0 h. Furthermore, the compounds Z-2a, Z-2b, Z-2c, Z-2e, Z-6a and Z-6d were effective at a medium dose of 100mg/kg at 0.5h, especially Z-2a and Z-2c, which were also effective at 4h, whereas the amide or lactam free molecule Z-6c provided anti-MES protection at the higher dose of 300 mg/kg.
2. Pentatetrazole convulsive score (scPTZ) test
Experimental compounds: compounds Z-2a, Z-2b, Z-2c, Z-2d, Z-2e, Z-6a, Z-6b, Z-6c, Z-6d, Z-10a, Z-10b, Z-10c, Z-10d and Phenytoin (Phenytoin), phenobarbital (Phenobarbital), ethosuximide (Ethosuximide) prepared in examples 1-13.
The testing method comprises the following steps: the scPTZ test is a model of epilepsy induced by intraperitoneal injection of a dose of pentatetrazole (85 mg/kg in mice). Mice were given 85 mg/kg of pentatetrazole subcutaneously at 0.5h and 4h after administration of 30, 100 and 300mg/kg of test compound (a dose that would give rise to continuous 5 s clonic convulsions in 97% or more of the mice) and were left alone in the cage and observed for 30 min, in order to be effective against continuous 5 s or more clonic convulsions, the drug was thought to be effective against the convulsions induced by pentatetrazole.
Evaluation of results: in the scPTZ screen, compounds Z-2b, Z-2c, Z-2e, Z-6c and Z-6d showed inhibitory activity, identifying agents that raise seizure threshold. In particular Z-2b, Z-2e and Z-6d have complete protection against seizures after 0.5 and 4 hours of administration at a dose of 100 mg/kg.
3. Neurotoxicity screening (NT)
Experimental compounds: compounds Z-2a, Z-2b, Z-2c, Z-2e, Z-6a, Z-6b, Z-6c, Z-6d, phenytoin (Phenytoin), phenobarbital (Phenobarbital), ethosuximide (Ethosuximide) prepared in examples 1-13.
The testing method comprises the following steps: the present experiment employs a spin stick assay to evaluate neurotoxicity. The experimental procedure was to inject the test compound into the abdominal cavity of the trained mice at doses of 30, 100, and 300mg/kg, and after administration of 0.5. 0.5h, the mice were placed on a wooden stick with a diameter of 3.2. 3.2 cm and a rotational speed of 6 revolutions per minute, and none of the mice were considered neurotoxic when they were held on the stick for 1 minute for 3 consecutive tests, whereas they were not. If the compound does not show activity in the MES and scPTZ models, no neurotoxicity test is performed.
Evaluation of results: in the neurotoxicity test, all test compounds showed no neurotoxicity at 30mg/kg after a time interval of 0.5 and 4 hours, wherein compounds Z-2b, Z-2c, Z-2e, Z-6b, Z-6c, Z-6d showed no neurotoxicity at 0.5 and 4 hours at 100mg/kg body weight, at a neurotoxicity dose of 300 mg/kg; furthermore, although compounds Z-2a and Z-6a showed toxicity at 0.5h at 100mg/kg, the neurotoxic dose was increased to 300mg/kg after 4h over time.
TABLE 1 anticonvulsant Activity of exemplary Compounds and neurotoxicity test results
Animals were examined 0.5 and 4.0 hours after injection. Dash (-) indicates no activity at the maximum dose (300 mg/kg); a maximum electroconvulsive experiment; b a tefrazole convulsive score experiment; c neurotoxicity experiments.
(II) quantitative anticonvulsant assessment experiments
Experimental compounds: z-6b.
The testing method comprises the following steps: median Effective Dose (ED) was quantitatively tested at peak effect (TPE, 1 h) using the mouse abdominal route 50 ) And median Toxic Dose (TD) 50 ). Testing ED 50 When the experiment was divided into 6 groups, 6 mice per group were dosed at 5,10,13,17,23,30 mg/kg; testing TD 50 When the experiment was divided into 5 groups, 6 mice per group were dosed at 100,132,173,228,300 mg/kg; experimental results ED was calculated by Bliss method 50 And TD (time division) 50 。
Evaluation of results: the test selects the most active compound Z-6b in the MES model for further testing of ED50 and TD50 values, and the results are shown in Table 2. Experiments show that Z-6b has the advantages of high efficiency and low toxicity, has high protection on an MES model, and has an ED50 value of <20.5 mg/kg and a protection index of >10.
TABLE 2 quantitative anticonvulsant assessment of Z-6b in MES model
a Time effect to peak;
b ED 50 : a median effective dose providing anticonvulsant protection in 50% of animals, in mg/kg;
c TD 50 : a median toxic dose that causes minimal neurotoxicity in 50% of animals, in mg/kg;
d PI: protection index (TD) 50 /ED 50 ）；
e 95% confidence intervals are given in brackets.
(III) patch clamp experiments
1. Cell culture
Isolation of expressed Na V 1.1 recombinant CHO-K1 cells and Na-expression V 1.2、Na V 1.3 and Na V 1.6 and replanting at low density. Stably transfected CHO-K1 cells and HEK-293 cells were supplemented with 10% fetal bovine serum and containedCultured in minimal alkaline medium with 1.2 mg/mL G418 to select transfected cells and at 37℃in a medium containing 5% CO 2 Is cultured in a humidified incubator. During passage of cells we first removed bad medium, washed cells with 1' -PBS, then 2 mL of Accutase solution was added and the plates were placed in a 37 ℃ incubator for 5 minutes. Immediately after cell separation, 9 ml of medium completely warmed at 37 ℃ was added. The cell suspension was added to a sterile pipette and the cells were gently homogenized to separate the cell aggregates. In order to maintain electrophysiological properties, the cell density must not exceed 80%. Expansion was performed by seeding 2.5% cells or 105 cells/ml was maintained and placed in a T75 flask (final volume: 15 ml).
2. Patch clamp recording experiments
The patch clamp technique experiment uses the cultured CHO-K1 cells and HEK-293 cells to carry out the whole cell voltage clamp experiment. Electrophysiological recordings (olympus IX71 japan) were obtained under visual control of a microscope. An amplifier (HEKA EPC10, germany) is used to record the electrophysiological signal. The offset potential is directly zero before the seal is formed. No leakage subtraction was performed. The battery is made of full cell capacitance compensation. Data was stored and analyzed using the PatchMaster software. All experiments were performed at room temperature. The drug should be applied directly to the cells using a rapid infusion system within a few seconds. Each compound perfused for more than 5 minutes, or until the current reached steady state levels. Extracellular solutions were as follows: 140 mM NaCl,4 mM KCl,1 mM MgCl 2 ，2 mM CaCl 2 5 mM D-glucose monohydrate, 10 mM hepes, ph=7.4 plus NaOH; internal pipette solution: 145 mM CsCl, 0.1 mM CaCl 2 、2 mM MgCl 2 10 mM NaCl, 0.5 mM Na2 GTP, 2 mM Mg ATP, 1.1 mM EGTA, 10 mM HEPES, pH 7.2 and CsOH. Cells were placed in solution and exposed to the drug or carrier for about 30 minutes before starting the experiment. The recording was run for 1 hour, resulting in 1.5 hours of contact with the drug. Na (Na) V 1.1 current was measured using a step pulse, the module comprising hyperpolarization to-130 mV and then increased to-40 mV in step increments of 10 mV over a period of 8 s. Every 20 seconds from the holding potential of-120 mVThe scheme is repeated. The peak amplitude of the inward current was measured. Initial and steady state suppression of Nav1.1 current was measured using a double pulse mode consisting of a series of two depolarization test pulses, 0mV, lasting 20 ms. Starting from a holding potential of-120 mV, the first depolarization test pulse is followed by a hyperpolarization adjustment interval pulse to half-deactivation voltage (8 s interval), followed by a 20ms recovery period of-120 mV, and then the second depolarization test pulse is set to 0mV for 20 ms. The pulse pattern was repeated every 20 seconds and the inward current peak amplitudes of the two test pulses were measured.
Based on electrophysiology studies, Z-6b was dependent on state Na V 1.1、Na V 1.2、Na V 1.3 and Na V The 1.6 sodium ion channel had little inhibition (less than 5%) and had no effect on the use-dependent nav1.2, nav1.3 and nav1.6 channels at 10 μm (about 10%). However, although Z-6b showed a weak state-dependent nav1.1 channel block (inhibition rate of 4.5%), it was significantly effective at 10 μm with a inhibition rate of 32.0%. The results of this study show that Z-6b has some selectivity in inhibiting NaV1.1 channels (compared to NaV1.2, naV1.3 and NaV1.6 channels) and hardly inhibits sodium channels in normal resting state. Thus, Z-6b is very toxic.
Finally, it should be noted that the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited to the above-mentioned embodiment, but may be modified or some of the technical features thereof may be replaced by other technical solutions described in the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A benzisoxazole heterocyclic compound, characterized in that: the structural general formula of the compound is shown as the following formula (II):
wherein R2 refers to pyrrolidine-2, 5-diketo, pyrrolidine-2-keton or 3, 4-dihydroquinoline-2 (1H) -keton, and the specific structural formula of the compound is one of the following formulas:
2. a process for producing a benzisoxazole-based heterocyclic compound according to claim 1, characterized in that: the structural general formula of the starting materials used for the compound of formula (II) is as follows:
the compound of the formula (II) is prepared by reacting an equimolar starting material of a compound of the formula (V) with one of substituted or unsubstituted pyrrolidine-2, 5-dione, pyrrolidine-2-ketone and 3, 4-dihydroquinolin-2 (1H) -one in an organic solvent, in an alkaline environment, under heating and under a catalyst condition.
3. The method for producing a benzisoxazole heterocyclic compound according to claim 2, wherein: the organic solvent is acetonitrile or DMF, and the alkaline condition is K 2 CO 3 Or NaH.
4. The method for producing a benzisoxazole heterocyclic compound according to claim 2, wherein:
the preparation method of the starting material compound of formula (V) comprises the following steps: reacting a compound of formula (IV) with a halogenating reagent in an organic solvent for 4-8h, and heating the obtained product in 20% sulfuric acid to remove carboxylic acid to obtain a starting material compound of formula (V), wherein the molar ratio of the compound of formula (IV) to the halogenating reagent is 1: (1-1.2), an organic solventIs glacial acetic acid, CCl 4 、 CHCl 3 DCM, dioxane or DMF, the halogenating reagent being Br 2 HBr, HCl or thionyl chloride, the compound of formula (IV) has the structural formula:
5. a pharmaceutical composition characterized by: comprising a therapeutically effective amount of an enantiomer, diastereomer, racemate or mixture thereof of a compound of claim 1, together with one or more pharmaceutically acceptable carrier materials and/or adjuvants.
6. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of a psychotic disorder.
7. Use of a compound or pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of a psychotic disorder, characterized in that: the mental system disease is epilepsy, and the epilepsy comprises epileptic grand mal, epileptic small mal, primary epilepsy and secondary epilepsy.
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