CN113651767A - Benzisoxazole heterocyclic compound and preparation method and application thereof - Google Patents

Benzisoxazole heterocyclic compound and preparation method and application thereof Download PDF

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CN113651767A
CN113651767A CN202111103035.4A CN202111103035A CN113651767A CN 113651767 A CN113651767 A CN 113651767A CN 202111103035 A CN202111103035 A CN 202111103035A CN 113651767 A CN113651767 A CN 113651767A
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王增涛
董士阳
黄翔
王甜甜
王辉
黄佳藤
庞荔丹
兰萍萍
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Jiangxi University of Traditional Chinese Medicine
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Abstract

The invention relates to a benzisoxazole heterocyclic compound and a preparation method and application thereof, wherein the structural formula of the benzisoxazole heterocyclic compound comprises formulas (I), (II) and (III), and a specific preparation method of the benzisoxazole heterocyclic compound is specifically provided. The derivatives have good anticonvulsant activity and can be used as antiepileptic drugs.

Description

Benzisoxazole heterocyclic compound and preparation method and application thereof
Technical Field
The invention belongs to the field of organic synthesis and pharmaceutical 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 cerebral neurons, and has the characteristics of paroxysmal and repeated attacks. In clinical application, various antiepileptic drugs are available, such as phenobarbital, carbamazepine, phenytoin sodium, and valproic acid. Although these drugs are capable of protecting patients from various epileptic convulsions to varying degrees, they have side effects and tolerance that prevent their use in long-term therapy. In order to improve the therapeutic effect and eliminate or reduce side effects, novel compounds having novel structural features and novel mechanisms of action are needed.
Disclosure of Invention
The invention aims to solve the problems and provide a benzisoxazole heterocyclic compound which has low toxicity and can treat epilepsy.
The invention is realized by the following technical scheme: a benzisoxazole heterocyclic compound has a structural general formula as shown in the following formulas (I), (II) and (III):
Figure 689384DEST_PATH_IMAGE001
；
wherein, R1 represents one of substituted or unsubstituted benzene ring, substituted or unsubstituted 5-12 membered aromatic heterocyclic ring containing N, O atom, and substituted or unsubstituted 5-13 membered saturated heterocyclic ring containing N, O atom;
r2 denotes a substituted or unsubstituted 5-to 13-membered saturated heterocyclic ring containing a secondary amino N atom;
r3 represents one of substituted or unsubstituted thiazolidine-2, 4-dione, thiothiazolidine-4-dione, imidazoline-2, 4-dione, 2,4, 6-pyrimidinetrione, 2-thiobarbituric acid and indol-2-dione.
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, hydroxyl, 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, and 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, hydroxyl, 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, and 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 material is shown as the following formulas (IV), (V) and (VI):
Figure 384939DEST_PATH_IMAGE002
wherein X is halogen.
Further, the compound of formula (I) is prepared by condensation reaction of equimolar initial material compound of formula (IV) and ammonia compound in organic solvent, wherein the ammonia compound is one of substituted or unsubstituted phenylamine, substituted or unsubstituted 5-12 membered aromatic heterocyclic primary amine containing N, O atom, substituted or unsubstituted 5-13 membered saturated heterocyclic primary amine containing N, O atom, the organic solvent is DCM, DMF or DMSO, and the condensation reaction is SOCl2An acid chloride method.
Further, the compound of formula (II) is prepared by the reaction of equimolar starting material compound of formula (V) with one of substituted or unsubstituted pyrrolidine-2, 5-dione, pyrrolidine-2-one, 3, 4-dihydroquinolin-2 (1H) -one, thiazolidine-2, 4-dione, thiothiazolidine-4-one, imidazoline-2, 4-dione, indol-2-one, 2,4, 6-pyrimidinetrione, 2-thiobarbituric acid and piperidine in organic solvent, alkaline environment, heating and catalyst condition;
the organic solvent is acetonitrile or DMF, and the alkaline condition is K2CO3Or NaH.
Further, the compound of formula (III) is prepared by reflux reaction of equimolar starting material of the compound of formula (VI) with one of substituted or unsubstituted thiazolidine-2, 4-dione, 2-thioxothiazolidin-4-one, imidazoline-2, 4-dione, 2,4, 6-pyrimidinetrione and 2-thiobarbituric acid group in acetic acid/sodium acetate system, or indole-2-keto group in piperidine/ethanol system.
Further, the starting material of the compound of formula (IV) is prepared by: mixing and stirring sodium hydroxide, hydroxylamine hydrochloride and ethanol uniformly, adding 4-hydroxycoumarin, heating and stirring at 75-85 ℃ for reaction for 12-18h, after the reaction is finished, recovering ethanol under reduced pressure, dissolving residues in an aqueous solution of sodium bicarbonate, filtering, adjusting the pH of filtrate to be 3-5 by using the aqueous solution of hydrochloric acid, filtering, washing a filter cake to be neutral by using water, and drying in a vacuum drying oven to obtain an initial substance compound shown in a formula (IV), wherein the molar ratio of the sodium hydroxide to the hydroxylamine hydrochloride to the 4-hydroxycoumarin is 1: (0.7-0.8).
The starting material compound of formula (V) is prepared by: reacting a starting material compound shown in the formula (IV) with a halogenating agent in an organic solvent for 4-8h, and heating and decarboxylating the obtained product in 20% sulfuric acid to obtain a starting material compound shown in the formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the halogenating agent is 1: (1-1.2), the organic solvent is glacial acetic acid or CCl4、 CHCl3DCM, dioxane or DMF, the halogenating agent being Br2HBr, HCl or thionyl chloride.
Preparation of starting Material Compound of formula (VI)The preparation method comprises the following steps: dissolving a starting material compound shown as a formula (V) and metallic sodium in absolute ethyl alcohol, stirring and carrying out reflux reaction, dissolving an obtained initial product in an organic solvent, then cooling to-78 ℃ under the protection of argon, stirring, and carrying out BBr3Adding an organic solvent into the reaction solution, stirring at-78 ℃ for reaction, dissolving the obtained product in the organic solvent, adding an oxidant, and stirring at room temperature for reaction to obtain a starting material compound of the formula (VI), wherein the molar ratio of the compound of the formula (V) to the metal sodium is 1: (0.4-0.5), primary product, BBr3The molar ratio of the organic solvent is 1:2, and the organic solvent is DCM or CHCl3The oxidant is pyridine dichromate or KMnO4、K2Cr2O7、KClO3Concentrated H2SO4、HNO3、MnO2Or H2O2。
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an enantiomer, diastereomer, racemate or mixture thereof of the above-mentioned heterocyclic benzisoxazole compound, together with one or more pharmaceutically acceptable carrier substances 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 grand mal epilepsy, petit mal epilepsy, primary epilepsy and secondary epilepsy.
The pharmaceutically acceptable carrier of the invention is selected from the following group: lactose, sucrose, dextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, corn starch, a lower alkyl ether of cellulose, potato starch, gums, syrup, peanut oil, olive oil, phospholipids, glyceryl monostearate, glyceryl distearate, fatty acids, fatty acid amines, colorants, preservatives, flavors, water, ethanol, propanol, physiological saline, glucose solution, or combinations thereof.
The pharmaceutically acceptable auxiliary materials are selected from the following groups: binders, fillers, diluents, disintegrants, suspensions, suspending agents, slow (controlled) release agents, lyoprotectants, coatings, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, tonicity adjusting agents, colorants, pigments, surfactants, emulsifiers, water-soluble bases, fat-soluble bases, oleaginous bases, porogens, gels, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.
The dosage of a compound of the invention to achieve a 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. The daily dose will generally be in the range 0.3mg to 100mg (typically 3mg to 50 mg) per day per kilogram of body weight, and the intravenous dose will be in the range 0.3mg to 1.0mg, which is suitable for administration as 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 0ng to 100mg per ml. A single dose may contain, for example, lmg to 10g of active ingredient. Thus, for injection, a single dose formulation such as a tablet or capsule containing, for example, lmg to 100mg, and which can be administered orally, may contain, for example, lmg to 1000mg, typically 10 to 600 mg. For the prophylaxis and/or treatment of the abovementioned disorders, the compounds of the formula I can be employed as medicaments per se, but they are preferably present in the form of a pharmaceutical composition with a compatible carrier.
Drawings
FIG. 1 is Na of Compound Z-6bV1.1 State-dependent (TP 1) blockade profile of the channel;
FIG. 2 is Na of Compound Z-6bV1.1 use-dependent (TP 2) blockade profile of the channel;
FIG. 3 is Na of Compound Z-6bV1.2 State-dependent (TP 1) blockade profiles of channels;
FIG. 4 is Na of Compound Z-6bV1.2 use-dependent (TP 2) blockade profiles of channels;
FIG. 5 is Na of Compound Z-6bV1.3 State-dependent (TP 1) blockade profiles of channels;
FIG. 6 is compound Z-6Na of bV1.3 use-dependent (TP 2) blockade profiles of channels;
FIG. 7 is Na of Compound Z-6bV1.6 State-dependent (TP 1) blockade profiles of channels;
FIG. 8 is Na of Compound Z-6bV1.6 channel usage dependent (TP 2) blockade study.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The preparation of the compound of formula (I) of the invention
Embodiments 1 to 5 provide a benzisoxazole heterocyclic compound, which has a general structural formula as shown in formula (I):
Figure 65319DEST_PATH_IMAGE003
。
example 1
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ] isoxazol-3-yl) -N-phenylacetamide (Z-2a), and its preparation method is:
(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 with stirring at 80 ℃ for 16 h. After completion of the reaction, 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, a solid was precipitated, filtered, the filter cake was washed with water to neutrality and dried in a vacuum drying oven to obtain 31.2 g of white solid Z-1 as a starting material, i.e., the compound of formula (IV), in 75% yield. Mp：127-129 ℃; 1H-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). 13C-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 C9H7NO3 ([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 conditions2(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, and Na was used to bind the organic phases2SO4Drying, evaporating the solvent, and reacting the resulting product with dry DCM and dry Et3N (1.0 equivalent), adding aniline (1.0 equivalent) dropwise under ice bath condition, stirring at room temperature for 6h, adding water to the reaction solution for extraction, combining organic layers, and adding anhydrous Na2SO4Drying, spin-drying, and purifying the final product by column chromatography to obtain white solid Z-2a (yield 42%); mp: 131-;1H-NMR (CDCl3, 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, CH2). ESI-HRMS calcd for C15H12N2O2 ([M+H]+): 253.0899; found: 253. 0976。
the structural formula is as follows:
Figure 310662DEST_PATH_IMAGE004
。
example 2
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ] isoxazol-3-yl) -N- (2-fluorophenyl) acetamide (Z-2b), and its preparation method is:
(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 with stirring at 75 ℃ for 12 h. After the reaction is finished, recovering ethanol under reduced pressure, dissolving the residue in 80 mL of 10% sodium bicarbonate, filtering, adjusting the pH of the filtrate to =3 by using 6 mol/L hydrochloric acid solution, precipitating a solid, filtering, washing a filter cake to be neutral by using water, and drying in a vacuum drying oven to obtain a white solid Z-1 which is the starting material compound of the formula (IV).
(2) Preparation of 2- (benzo [ d ] isoxazol-3-yl) -N- (2-fluorophenyl) acetamide (Z-2 b):
referring to the synthesis method of example 1, the difference from example 1 is that the organic solvent in this example is DMF and the ammonia compound is 2-fluoroaniline, yielding Z-2b (yield 40%) as a white solid; mp 140-;1H-NMR (CDCl3, 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, CH2). ESI-HRMS calcd for C15H11FN2O2 ([M+H]+): 271.0805; found: 271.0879。
the structural formula is as follows:
Figure 14176DEST_PATH_IMAGE005
。
example 3
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ] isoxazol-3-yl) -N- (3-chlorophenyl) acetamide (Z-2c), and its preparation method is:
(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 with stirring at 85 ℃ for 18 h. After the reaction is finished, recovering ethanol under reduced pressure, dissolving the residue in 80 mL of 10% sodium bicarbonate, filtering, adjusting the pH of the filtrate to =5 by using 6 mol/L hydrochloric acid solution, precipitating a solid, filtering, washing a filter cake to be neutral by using water, and drying in a vacuum drying oven to obtain a white solid Z-1 which is the starting material compound of the formula (IV).
(2) Preparation of 2- (benzo [ d ] isoxazol-3-yl) -N- (3-chlorophenyl) acetamide (Z-2 c):
referring to the synthesis method of example 1, the difference from example 1 is that the organic solvent in this example is DMSO, the ammonia compound is 3-chloroaniline, and light yellow solid Z-2c (yield 67%) is obtained; mp 160-;1H-NMR (CDCl3, 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, CH2). ESI-HRMS calcd for C15H11ClN2O2([M+H]+): 287.0509; found: 287.0579。
the structural formula is as follows:
Figure 247843DEST_PATH_IMAGE006
。
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-2d), prepared according to the synthesis of example 1, differing from example 1 in that the ammonia compound in this example is 4-tert-butylaniline, giving Z-2d (yield 22%) as a light brown solid; mp 102-;1H-NMR (CDCl3, 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, CH2) , 1.30 (s, 9H, 3CH3)。
the structural formula is as follows:
Figure 782729DEST_PATH_IMAGE007
。
example 5
This example provides a benzisoxazole heterocyclic compound, which is named 2- (benzo [ d ]]Isoxazol-3-yl) -N- (2, 6-difluorophenyl) acetamide (Z-2e), prepared according to the synthesis method of example 1, differing from example 1 in that the ammoniacal compound in this example is 2, 6-dichloroaniline, giving Z-2e (yield 53%) as a white solid; mp is 192 ℃ and 194 ℃;1H-NMR (CDCl3, 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, CH2). ESI-HRMS calcd for C15H10F2N2O2 ([M+H]+): 289.0710; found: 289.0784。
the structural formula is as follows:
Figure 473342DEST_PATH_IMAGE008
。
secondly, the preparation of the compound of formula (II) of the invention
Examples 6 to 9 provide benzisoxazole heterocyclic compounds having a general structural formula as shown in formula (II):
Figure 460890DEST_PATH_IMAGE009
。
the synthesis process of the compound of formula (II) is as follows:
Figure 763826DEST_PATH_IMAGE010
。
example 6
This example provides a benzisoxazole heterocyclic compound, which is named 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidine-2, 5-dione (Z-6a), and its preparation method is:
(1) a process for preparing a starting material, a compound of formula (V) (Z-5):
compound Z-1 (1.42.0 g, 8.0 mmol) synthesized above was dissolved in 5mL of glacial acetic acid, bromine (0.45 mL, 8.8 mmol) was added dropwise slowly with stirring (dropping time 30 min), reacted at room temperature for 6h, then the reaction solution was poured into ice water (20 mL), stirred, the solid precipitated, filtered, and the filter cake was dried to give Z-4 (1.74 g, yield 85%) as a pale yellow solid. Compound Z-4 (1.74 g, 6.8 mmol) was dissolved in 20% sulfuric acid (6 mL), refluxed for 4h with stirring, then cooled to room temperature, filtered and steam distilled to obtain 1.28g of white crystalline Z-5, which is the compound of formula (V) in 76% yield. mp is 61-62 ℃;1H-NMR (CDCl3, 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, CH2). ESI-HRMS calcd for C8H6BrNO ([M+H]+): 211.9633; found: 211.9704。
(2) preparation of 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidine-2, 5-dione (Z-6 a):
the compound Z-5 (1.0 equivalent) synthesized above and K2CO3(2.0 equiv.) and catalytic equivalent KI were mixed well, a mixed solution of DMF and pyrrolidine-2, 5-dione was added dropwise and reacted at 80 ℃ overnight, 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 anhydrous Na was used2SO4Drying, spin-drying, and purifying the final product by column chromatography to obtain brown solid Z-6a (yield 67%); mp 181 ℃ and 183 ℃;1H-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, CH2), 2.74 (s, 4H, 2CH2). ESI-HRMS calcd for C12H10N2O3 ([M-H]+): 231.0691; found: 231.0764。
the structural formula is as follows:
Figure 670996DEST_PATH_IMAGE011
。
example 7
This example provides a benzisoxazole heterocyclic compound, which is named 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidin-2-one (Z-6b), and its preparation method is:
(1) a process for preparing a starting material, a compound of formula (V) (Z-5):
compound Z-1 (1.42.0 g, 8.0 mmol) synthesized above was dissolved in 5mLCCl4To the reaction solution was slowly added dropwise under stirring, HBr (8.8 mmol), reacted at room temperature for 4 hours, and then the reaction solution was poured into ice water (20 ml), stirred, precipitated a solid, filtered, and the filter cake was dried to give Z-4 as a pale yellow solid. Compound Z-4 (1.74 g, 6.8 mmol) was dissolved in 20% sulfuric acid (6 mL), refluxed for 4h with stirring, then cooled to room temperature, filtered and distilled with steam to obtain 1.28g of white crystalline Z-5, which is the compound of formula (V).
(2) Preparation of 1- (benzo [ d ] isoxazol-3-ylmethyl) pyrrolidin-2-one (Z-6 b):
uniformly mixing the synthesized compound Z-5 (1.0 equivalent), NaH (2.0 equivalent) and catalytic equivalent KI, dropwise adding a mixed solution of acetonitrile and pyrrolidine-2-ketone, reacting at 80 ℃ overnight, after the reaction is finished (TLC monitoring), pouring the reaction solution into cold water, extracting with ethyl acetate, combining organic layers, and adding anhydrous Na2SO4Drying, spin-drying, and purifying the final product by column chromatography to obtain colorless oily liquid Z-6b (yield 56%);1H-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, CH2), 3.33 (t, 1H, J = 7.2 Hz, CH2), 2.31 (t, 2H, J = 7.8 Hz, CH2), 1.89-1.95 (m, 3H, CH3). ESI-HRMS calcd for C12H12N2O2 ([M+Na]+): 239.0796; found: 239.0794。
the structural formula is as follows:
Figure 548822DEST_PATH_IMAGE012
。
example 8
This example provides a benzisoxazole heterocyclic compound, which is named 3- (piperidin-1-ylmethyl) benzo [ d ] isoxazole (Z-6c), and its preparation method is:
(1) a process for preparing a starting material, a compound of formula (V) (Z-5):
compound Z-1 (1.42.0 g, 8.0 mmol) synthesized above was dissolved in 5mL of EDCM, bromine (0.45 mL, 8.8 mmol) was slowly added dropwise with stirring, and reacted at room temperature for 8h, then the reaction solution was poured into ice water (20 mL), stirred, a solid precipitated, filtered, and the filter cake was dried to give Z-4 as a pale yellow solid. Compound Z-4 (1.74 g, 6.8 mmol) was dissolved in 20% sulfuric acid (6 mL), refluxed for 4h with stirring, then cooled to room temperature, filtered and distilled with steam to obtain 1.28g of white crystalline Z-5, which is the compound of formula (V).
(2) Preparation of 3- (piperidin-1-ylmethyl) benzo [ d ] isoxazole (Z-6 c):
uniformly mixing the synthesized compound Z-5 (1.0 equivalent), NaH (2.0 equivalent) and catalytic equivalent KI, dropwise adding a mixed solution of acetonitrile and piperidine, stirring at 60 ℃ for reaction for 3 hours, after the reaction is finished (monitoring by TLC), pouring the reaction solution into cold water, extracting with ethyl acetate, combining organic layers, and adding anhydrous Na2SO4Drying, spin-drying, and purifying the final product by column chromatography to obtain pale yellow solid Z-6c (yield 74%); mp is 80-82 ℃;1H-NMR (CDCl3, 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, CH2), 2.54 (s, 4H, 2CH2), 1.61-1.65 (m, 4H, 2CH2), 1.42-1.51 (m, 2H, CH2). ESI-HRMS calcd for C13H16N2O ([M+H]+): 217.1263; found: 217.1331。
the structural formula is as follows:
Figure 305557DEST_PATH_IMAGE013
。
example 9
This example provides a benzisoxazole heterocyclic compound, which is named 1- (benzo [ d ] isoxazol-3-ylmethyl) -3, 4-dihydroquinolin-2 (1H) -one (Z-6d), and its preparation method is:
(1) reference is made to example 1 for a process for the preparation of the starting compound of formula (V) (Z-5), which differs from example 1 in that the organic solvent is DMF.
(2) 1- (benzo [ d ]]Preparation of isoxazol-3-ylmethyl) -3, 4-dihydroquinolin-2 (1H) -one (Z-6 d): the compound Z-5 (1.0 equivalent) synthesized above and K2CO3(2.0 equiv.) and catalytic equivalent KI were mixed well, a mixed solution of DMF and 3, 4-dihydroquinolin-2 (1H) -one was added dropwise and reacted at 80 ℃ overnight, 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 anhydrous Na was used2SO4Drying, spin-drying, and purifying the final product by column chromatography to obtain white solid Z-6d (yield 54%); mp is 71-73 ℃;1H-NMR (CDCl3, 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, CH2), 2.96 (t, 2H, J = 7.8 Hz, CH2), 2.80 (t, 2H, J = 7.8 Hz, CH2). ESI-HRMS calcd for C17H14N2O2 ([M+H]+): 279.1055; found: 279.1123。
the structural formula is as follows:
Figure 176298DEST_PATH_IMAGE014
。
thirdly, the preparation of the compound of the formula (III) of the invention
Examples 10-13 provide a benzisoxazole heterocyclic compound having a general structural formula as shown in formula (III):
Figure 702089DEST_PATH_IMAGE015
。
the synthesis process of the compound of formula (III) is as follows:
Figure 485237DEST_PATH_IMAGE016
。
example 10
This example provides a benzisoxazole heterocyclic compound, which is named 5- (benzo [ d ] isoxazol-3-ylmethylene) thiazolidine-2, 4-dione (Z-10a), and its preparation method is:
the method comprises the following steps: compound Z-5 (800 mg, 3.8 mmol) synthesized above 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 obtain 0.27 g of a white crystalline product Z-7 with a yield of 40%.1H-NMR (CDCl3, 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, CH2), 3.47 (s, 2H, CH3)。
Step two: dissolving the compound Z-7 (380 mg, 2.1 mmol) in DCM (3 mL), then cooling to-78 ℃ under the protection of argon and stirring for 30 min, and reacting BBr3(1.08 g, 4.2 mmol) and DCM (3 mL) were added to the above reaction solution and the reaction was stirred at-78 ℃ for 30 h. After completion of the reaction, the reaction was allowed to warm to room temperature and filtered, and the solvent was removed by evaporation to obtain 0.28 g of crystalline Z-8 in 88% yield. mp is 71-73 ℃;1H-NMR (CDCl3, 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, CH2); 13C NMR (151 MHz, CDCl3) 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 the oxidant pyridine dichromate (3.8 g, 10 mmol) 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 eluents to give 166 mg of product Z-9 in 34% yield.1H-NMR (CDCl3, 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 compound Z-9 (0.07 mmol) synthesized above and thiazolidine-2, 4-dione (0.07 mmol) were mixed uniformly in the presence of sodium acetate (2.24 g, 0.4 mol) using acetic acid (7 mL) as a solvent, reacted under reflux with intermittent stirring for 3h, and the reaction was monitored by thin layer chromatography using n-hexane and ethyl acetate as mobile phases at a ratio of 1: 1. After completion of the reaction, the reaction mixture was cooled to obtain a crystalline product, which was then filtered with a pump, washed with water, and dried, and recrystallized from ethanol to yield Z-10a (yield 79%) as a yellow solid; mp is 236 ℃;1H-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:
Figure 230733DEST_PATH_IMAGE017
。
example 11
This example provides a benzisoxazole heterocyclic compound, which is named 5- (benzo [ d ]]Isoxazol-3-ylmethylene) -2-thioxothiazolidin-4-one (Z-10b) prepared according to the synthesis of example 10, differing from example 10 in that: in this embodiment, the organic solvent in the second and third steps is CHCl3The oxidant in the third step is KMnO4And in the fourth step, the compound Z-9 and 2-thiothiazolidine-4-ketone are subjected to reflux reaction for 2 hours.
Finally obtaining yellow solid Z-10b (yield 90%);1H-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 C11H6N2O2S2 ([M+H]+): 262.9871; found: 262.9945。
the structural formula is as follows:
Figure 672209DEST_PATH_IMAGE018
。
example 12
This example provides a benzisoxazole heterocyclic compound, which is named 5- (benzo [ d ]]Isoxazol-3-ylmethylene) imidazoline-2, 4-dione (Z-10c), which was prepared according to the synthesis method of example 10 and differs from example 10 in that: in this example, the oxidant in step three is K2Cr2O7And in the fourth step, the compound Z-9 and imidazoline-2, 4-diketone carry out reflux reaction for 4 hours.
Finally obtaining yellow solid Z-10c (yield 20%); 255 ℃ and 257 ℃ for mp;1H-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 C11H7N3O3 ([M+H]+): 230.0487;found: 230.0564。
the structural formula is as follows:
Figure 613358DEST_PATH_IMAGE019
。
example 13
This example provides a benzisoxazole heterocyclic compound, which is named 3- (benzo [ d ] isoxazol-3-ylmethylene) indol-2-one (Z-10d), and the preparation method thereof refers to the synthesis method of example 10, which is different from example 10 in that the specific steps of step four in this example are:
a mixture of compound Z-9 (61 mg, 0.5 mmol) synthesized above, indol-2-one (61 mg, 0.4 mmol), piperidine (26 mg, 0.3 mmol) and ethanol (3 mL) was reacted in a round-bottomed flask under reflux for 3h, then the reaction mixture was poured into water (10 mL) and acidified with acetic acid and recrystallized from methanol to give Z-10d (yield 56%) as a yellow solid;1H-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 C16H10N2O2 ([M+H]+): 263.0742; found: 263.0815。
the structural formula is as follows:
Figure 318140DEST_PATH_IMAGE020
。
application of compound of the invention in treating epilepsy
In the experiment of the invention, the tested animals are all male mice (Kunming mouse species, 20-25 g).
Anticonvulsant Activity screening and neurotoxicity testing of Compounds
Anticonvulsant activity of compounds was evaluated using two models, the maximum electroconvulsive test (MES) and the convulsant trap test (scPTZ), with reference to the "Antiepileptic Drug Development Program (anti) published by the national institute of health (NIN) of america. Neurotoxicity screening was assessed by the rotarod method. The results of the anticonvulsant activity and neurotoxicity screening 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 the compound is effective in the MES model, it indicates that the compound has an anti-seizure effect.
Test compounds: the 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 (phenoytoin), Phenobarbital (Phenobarbital), Ethosuximide (Ethosuximide) prepared in examples 1 to 13.
The test method comprises the following steps: mice were placed under temperature-controlled conditions (25-30 ℃) and fed for 24 hours, during which time they were free to gain food and water to acclimatize, and then were pre-screened the day before the formal experiment, at which time the ear electrodes of the mice were energized for 0.3s, and mice with convulsions were used for the formal experiment. In the official experiment, the tested compound was not effective when the ear electrode was electrified for 0.3s at 0.5h and 4h after the test compound was administered, and the convulsion was recognized as the appearance of a strong hind limb. Absence of hindlimb rigidity was recorded as anticonvulsant activity. The test article was prepared by dissolving the compound in 50% aqueous polyethylene glycol solution. In the MES screen, the number of mice per 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 of 2-3 mice that experienced no convulsions after administration in the same test mouse dose group.
And (4) evaluating the result: most compounds show some activity in MES experiments. The most active Z-6b showed a high seizure protection at a minimum dose of 30mg/kg at 0.5h, indicating that this compound has good properties of rapid onset at lower doses. Also, Z-6b was active at a higher dose of 100mg/kg at 4.0 h. Furthermore, the compounds Z-2a, Z-2b, Z-2c, Z-2e, Z-6a and Z-6d are effective at a moderate dose of 100mg/kg at 0.5h, in particular Z-2a and Z-2c, which are also effective at 4h, whereas the molecule Z-6c, which does not contain an amide or lactam group, provides protection against MES at a higher dose of 300 mg/kg.
2. Switzetrazole Metal cascades (scPTZ) test
Test compounds: the 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 (phenoytoin), Phenobarbital (Phenobarbital), Ethosuximide (Ethosuximide) prepared in examples 1 to 13.
The test method comprises the following steps: the scPTZ test is a model of epilepsy induced by intraperitoneal injection of a dose of pentylenetetrazol (85 mg/kg in mice). The mice were subcutaneously administered with 85 mg/kg of pentylenetetrazol (which dose resulted in clonic convulsions of 5 s continuously in more than 97% of the mice) at 0.5h and 4h after administration of 30, 100 and 300mg/kg of the test compound, and the mice were individually placed in mouse cages for 30 min, and it was considered that the drug was effective against convulsions induced by pentylenetetrazol in the absence of clonic convulsions of 5 s continuously or more.
And (4) evaluating the result: in the scPTZ screen, compounds Z-2b, Z-2c, Z-2e, Z-6c and Z-6d showed inhibitory activity and could identify substances that increased seizure threshold. In particular Z-2b, Z-2e and Z-6d, have a complete protective effect against epileptic seizures after 0.5 and 4 hours of administration at a dose of 100 mg/kg.
3. Neurotoxicity screening (NT)
Test compounds: the compounds Z-2a, Z-2b, Z-2c, Z-2e, Z-6a, Z-6b, Z-6c, Z-6d prepared in examples 1-13, and Phenytoin (phenoytoin), Phenobarbital (Phenobarbital), Ethosuximide (Ethosuximide).
The test method comprises the following steps: the present experiment used a rotarod test to assess neurotoxicity. Experimental methods the test compounds were injected intraperitoneally at doses of 30, 100, and 300mg/kg into trained mice, 0.5h after administration, the mice were placed on wooden bars with a diameter of 3.2 cm and a rotation speed of 6 revolutions/min, and no mice were considered neurotoxic when they remained on the wooden bars for 1 min and were lost in 3 consecutive tests, whereas no neurotoxicity was observed. If the compound showed no activity in the MES and scPTZ models, it was not tested for neurotoxicity.
And (4) evaluating the result: in the neurotoxicity test, all the tested compounds showed no neurotoxicity at 30mg/kg after a time interval of 0.5 and 4h, with the compounds Z-2b, Z-2c, Z-2e, Z-6b, Z-6c, Z-6d showing no neurotoxicity at 0.5 and 4h at the administration of 100mg/kg body weight, at a neurotoxicity dose of 300 mg/kg; furthermore, although compounds Z-2a and Z-6a showed toxicity at 100mg/kg at 0.5h, the neurotoxic dose was increased to 300mg/kg over time to 4 h.
TABLE 1 results of anticonvulsant Activity and neurotoxicity testing of exemplified Compounds
Figure 285353DEST_PATH_IMAGE021
Animals were examined 0.5 and 4.0 hours after injection. Dash (-) indicates no activity at the maximum dose (300 mg/kg);amaximum electroconvulsive experiment;ba hittrazole convulsion experiment;cneurotoxicity experiments.
(II) quantitative anticonvulsant evaluation test
Test compounds: z-6 b.
The test method comprises the following steps: the median Effective Dose (ED) was quantitatively determined at peak effect (TPE, 1 h) using the intraperitoneal route in mice50) And a centrally Toxic Dose (TD)50). Testing ED50At the same time, the experiment was divided into 6 groups of 6 mice each, dosed at 5,10,13,17,23,30 mg/kg; testing TD50At the time, the experiment was divided into 5 groups of 6 mice per group, dosed at 100,132,173,228,300 mg/kg; experimental results ED was calculated by Bliss method50And TD50。
And (4) evaluating the result: the most active compound Z-6b in the MES model was selected for further testing the ED50 and TD50 values, the results of which 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 less than 20.5 mg/kg and a protection index of more than 10.
TABLE 2 quantitative anticonvulsant evaluation of Z-6b in MES model
Figure 514209DEST_PATH_IMAGE022
aTime effect to peak;
b ED50: a median effective dose in the form of m to provide anticonvulsant protection in 50% of animalsg/kg；
c TD50: a median toxic dose in mg/kg that causes minimal neurotoxicity in 50% of the animals;
dPI: protection index (TD)50/ED50）；
eThe 95% confidence intervals are given in parentheses.
(III) patch-clamp experiment
1. Cell culture
Isolation of expression of NaV1.1 recombinant CHO-K1 cells and expression of NaV1.2、NaV1.3 and NaV1.6, and replanting at low density. Stably transfected CHO-K1 and HEK-293 cells were cultured in minimal alkaline medium supplemented with 10% fetal bovine serum and containing 1.2 mg/mL G418 to select transfected cells and incubated at 37 ℃ in a medium containing 5% CO2The culture in a humidified incubator. During cell passaging, we first removed the bad medium, washed the cells with 1' -PBS, then added 2 mL of Accutase solution, and placed the plates in a 37 ℃ incubator for 5 minutes. Immediately after cell separation, 9 mL of 37 ℃ completely pre-warmed medium was added. The cell suspension was added to a sterile pipette and the cells were gently homogenized to separate cell aggregates. In order to maintain electrophysiological properties, the cell density should not exceed 80%. 105 cells/ml were expanded or maintained by seeding 2.5% of the cells, and placed in a T75 flask (final volume: 15 ml).
2. Patch clamp recording experiment
The CHO-K1 cell and HEK-293 cell cultured as above were used for whole cell voltage clamp experiments. Electrophysiological recordings were obtained under visual control of a microscope (olympus IX71, japan). Amplifiers (HEKA EPC10, germany) are used for recording electrophysiological signals. The offset potential is directly zero before the seal is formed. No leakage subtraction was performed. The battery is made by full battery capacitance compensation. The 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 within a few seconds using a rapid perfusion system. Perfusion per compoundOver 5 minutes, or until the current reaches a steady state level. Extracellular solutions were as follows: 140 mM NaCl, 4 mM KCl, 1 mM MgCl2，2 mM CaCl25 mM D-glucose monohydrate, 10 mM HEPES, pH =7.4 plus NaOH; internal pipette solution: 145 mM CsCl, 0.1 mM CaCl2、2 mM MgCl210 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 vehicle for about 30 minutes before starting the experiment. The recording was run for 1 hour, resulting in 1.5 hours of exposure to the drug. Na (Na)V1.1 Current was measured using a step pulse, which included hyperpolarization to-130 mV, then increasing to-40 mV in 10 mV step increments over a period of 8 s. The protocol was repeated every 20 seconds starting with a holding potential of-120 mV. The peak amplitude of the inward current is measured. Initial and steady state inhibition of Nav1.1 current was measured using a double pulse pattern consisting of a series of two depolarizing test pulses, 0mV, lasting 20 ms. Starting with a holding potential of-120 mV, the first depolarization test pulse was followed by a hyperpolarization conditioning interval pulse to a semi-inactivating voltage (8 s interval), followed by a 20ms recovery period of-120 mV, and then the second depolarization test pulse was set at 0mV for 20 ms. The pulse pattern was repeated every 20 seconds and the peak amplitude of the inward current of the two test pulses was measured.
From the results of electrophysiological studies, Z-6b is state-dependent on NaV1.1、NaV1.2、NaV1.3 and NaV1.6 sodium ion channels have little inhibition (inhibition less than 5%), and at 10. mu.M there is no effect on the use of dependent NaV1.2, NaV1.3 and NaV1.6 channels (inhibition of about 10%). However, although Z-6b showed a weak state-dependent nav1.1 channel block (inhibition of 4.5%), it was significantly effective at 10 μ M using a dependent nav1.1 channel block, which reached 32.0%. The results of this study show that Z-6b has some selectivity in inhibiting the nav1.1 channel (compared to nav1.2, nav1.3 and nav1.6 channels) and hardly inhibits the sodium channel under normal resting conditions. Thus, Z-6b is less toxic.
Finally, it should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and not intended to limit the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or some technical features thereof can be replaced. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A benzisoxazole heterocyclic compound, characterized in that: the structural general formula of the compound is shown as the following formulas (I), (II) and (III):
Figure 910564DEST_PATH_IMAGE001
；
wherein, R1 represents one of substituted or unsubstituted benzene ring, substituted or unsubstituted 5-12 membered aromatic heterocyclic ring containing N, O atom, and substituted or unsubstituted 5-13 membered saturated heterocyclic ring containing N, O atom;
r2 denotes a substituted or unsubstituted 5-to 13-membered saturated heterocyclic ring containing a secondary amino N atom;
r3 represents one of substituted or unsubstituted thiazolidine-2, 4-dione, thiothiazolidine-4-dione, imidazoline-2, 4-dione, 2,4, 6-pyrimidinetrione, 2-thiobarbituric acid and indol-2-dione.
2. The benzisoxazole heterocyclic compound according to claim 1 which is characterized in that:
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, hydroxyl, 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, hydroxyl, 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, and substituted or unsubstituted C1-C4 sulfonyl.
3. A method for producing the benzisoxazole heterocyclic compound according to claim 1, which is characterized in that: the structural general formula of the used starting material is shown as the following formulas (IV), (V) and (VI):
Figure 162684DEST_PATH_IMAGE002
wherein X is halogen.
4. The method for producing a benzisoxazole heterocyclic compound according to claim 3, characterized in that: the compound of the formula (I) is prepared by condensation reaction of equimolar initial material compound of the formula (IV) and ammonia compound in an organic solvent, wherein the ammonia compound is one of substituted or unsubstituted phenylamine, substituted or unsubstituted primary 5-12-membered aromatic heterocyclic ring containing N, O atoms and substituted or unsubstituted primary 5-13-membered saturated heterocyclic ring containing N, O atoms, the organic solvent is DCM, DMF or DMSO, and the condensation reaction is SOCl2An acid chloride method.
5. The method for producing a benzisoxazole heterocyclic compound according to claim 3, characterized in that: the compound of the formula (II) is prepared by reacting equimolar starting materials of a compound of a 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, indol-2-ketone, 2,4, 6-pyrimidinetrione, 2-thiobarbituric acid and piperidine in an organic solvent under the conditions of alkaline environment, heating and a catalyst;
the organic solvent is acetonitrile or DMF, and the alkaline condition is K2CO3Or NaH.
6. The method for producing a benzisoxazole heterocyclic compound according to claim 3, characterized in that: the compound of the formula (III) is prepared by reflux reaction of equimolar starting material compound of the formula (VI) and one of substituted or unsubstituted thiazolidine-2, 4-diketone, 2-thio thiazolidine-4-ketone, imidazoline-2, 4-diketone, 2,4, 6-pyrimidinetrione and 2-thio barbituric acid in an acetic acid/sodium acetate system, or reflux reaction of indole-2-ketone in a piperidine/ethanol system.
7. The method for producing a benzisoxazole heterocyclic compound according to claim 3, characterized in that:
the starting material of the compound of formula (IV) is prepared by the following steps: mixing and stirring sodium hydroxide, hydroxylamine hydrochloride and ethanol uniformly, adding 4-hydroxycoumarin, heating and stirring at 75-85 ℃ for reaction for 12-18h, after the reaction is finished, recovering ethanol under reduced pressure, dissolving residues in an aqueous solution of sodium bicarbonate, filtering, adjusting the pH of filtrate to be 3-5 by using the aqueous solution of hydrochloric acid, filtering, washing a filter cake to be neutral by using water, and drying in a vacuum drying oven to obtain an initial substance compound shown in a formula (IV), wherein the molar ratio of the sodium hydroxide to the hydroxylamine hydrochloride to the 4-hydroxycoumarin is 1: (0.7-0.8);
the starting material compound of formula (V) is prepared by: reacting a starting material compound shown in the formula (IV) with a halogenating agent in an organic solvent for 4-8h, and heating and decarboxylating the obtained product in 20% sulfuric acid to obtain a starting material compound shown in the formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the halogenating agent is 1: (1-1.2), the organic solvent is glacial acetic acid or CCl4、 CHCl3DCM, dioxane or DMF, the halogenating agent being Br2HBr, HCl or thionyl chloride;
the starting material compound of formula (VI) is prepared by the following steps: dissolving the starting material of the formula (V) and sodium metal in absolute ethanol, stirring andreflux reaction, dissolving the obtained initial product in an organic solvent, cooling to-78 ℃ under the protection of argon, stirring, and reacting BBr3Adding an organic solvent into the reaction solution, stirring at-78 ℃ for reaction, dissolving the obtained product in the organic solvent, adding an oxidant, and stirring at room temperature for reaction to obtain a starting material compound of the formula (VI), wherein the molar ratio of the compound of the formula (V) to the metal sodium is 1: (0.4-0.5), primary product, BBr3The molar ratio of the organic solvent is 1:2, and the organic solvent is DCM or CHCl3The oxidant is pyridine dichromate or KMnO4、K2Cr2O7、KClO3Concentrated H2SO4、 HNO3、MnO2Or H2O2。
8. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of an enantiomer, diastereomer, racemate of a compound of claim 1, or mixture thereof, together with one or more pharmaceutically acceptable carrier substances and/or adjuvants.
9. Use of a compound or pharmaceutical composition according to claim 1 or 8 for the treatment of a psychiatric disorder.
10. The compound or pharmaceutical composition according to claim 9 for use in the treatment of a psychiatric disorder, wherein: the mental system disease is epilepsy, and the epilepsy comprises grand mal epilepsy, petit mal epilepsy, primary epilepsy and secondary epilepsy.
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