CN114149395A - A kind of benzocyclopentenone derivative, its preparation method and medical use - Google Patents

Abstract

The invention relates to a benzo-cyclopentenone derivative, a preparation method and medical application thereof. The compound has excellent protective effect on cerebral cortex neuron cells, and can remarkably improve the survival rate of the cerebral cortex neuron cells under the condition of oxygen deficiency and sugar deficiency. The compound of the invention has simple synthesis method and cheap and easily obtained raw materials, thereby being suitable for industrialized application.

Description

Benzo cyclopentenone derivative, preparation method and medical application thereof

Technical Field

The invention relates to the field of medicines, in particular to a benzo-cyclopentenone derivative, a preparation method and medical application thereof.

Background

Cardiovascular and cerebrovascular diseases are the first killers causing death of the middle-aged and elderly people in China, and are also one of the key points of the worldwide strategic health research. The stroke can be classified into hemorrhagic and ischemic ones, and the latter accounts for about 87% of stroke patients. Once stroke occurs, it will bring heavy economic and mental burden to the family of patients. The acute cerebral ischemic diseases have the characteristics of high disability rate, high death rate and high recurrence rate. According to statistics of a Chinese stroke prevention and treatment report 2019, the stroke standardization prevalence rate of people over 40 years old in China in 2012 is 1.89%, the stroke standardization prevalence rate of people over 2018 is increased to 2.32%, the stroke prevalence rate of people over 40 years old and over in China is calculated to be 1318 ten thousand, the stroke is already the 1 st death cause of the nation, and at least 1 of 5 death people dies from the stroke. However, the pathological mechanism of ischemic brain injury is complex, the research progress is slow, so far there are few internationally recognized treatment drugs, and effective preventive drugs and preventive measures are also very lacking. Therefore, the development of the medicine for resisting the cerebral apoplexy has huge clinical requirements and important social significance.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a benzo-cyclopentenone derivative which can remarkably improve the survival rate of cerebral cortex neuron cells under the condition of oxygen deficiency and sugar deficiency and has a strong protective effect.

Accordingly, a first aspect of the present invention provides a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof:

wherein:

x is selected from-O-, -NR₄-、-CR₅R₆-any of;

R₀、R₁each independently selected from any one of hydrogen, C1-C10 alkyl, C3-C12 cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

R₂selected from hydrogen, halogen, hydroxy, C1-6 alkoxy, nitro, -ONO₂Any one of the above;

l is selected from C1-C10 alkylene optionally substituted with one or more groups selected from halogen, hydroxy, nitro, amino;

R₃each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C6-C14 aryl;

m is selected from 0,1, 2 or 3, and when m is 2 or 3, each R₃May be the same or different;

R₄selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl;

R₅、R₆each independently selected from hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or R₅、R₆Together with the carbon atom to which they are attached form a C3-8 cycloalkyl group;

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alone or as part of any group, is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C3-C8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-2 alkylC 6-C10 aryl, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

A second aspect of the present invention provides a pharmaceutical composition comprising at least one benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof.

A third aspect of the present invention provides the use of a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof, for the preparation of a neuroprotective agent, a platelet aggregation inhibitor or an antioxidant medicament.

The third aspect of the present invention also provides the use of the benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof, for the preparation of a medicament for the prevention and treatment of neurodegenerative diseases or ischemic diseases. Preferably, the neurodegenerative diseases comprise senile dementia, Parkinson and the like; the ischemic diseases include myocardial ischemia and cerebral apoplexy.

To this end, the third aspect of the present invention also provides the use of a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof, for the preparation of a medicament for the prevention and treatment of myocardial ischemia and stroke, or for the treatment associated with the convalescent phase of stroke.

In a fourth aspect the present invention provides a process for the preparation of a benzocyclopentenone derivative of formula I.

Has the advantages that:

the benzo cyclopentenone derivative has excellent protective effect on cerebral cortex neuron cells, and particularly can remarkably improve the survival rate of the cerebral cortex neuron cells under the condition of oxygen deficiency and sugar deficiency; in addition, the compound has excellent brain protection effect and can greatly reduce the cerebral infarction area. Meanwhile, the effect of the compound is superior to that of the positive drugs edaravone and senkyunolide I. Therefore, the compound can be used for preparing neuroprotective agents, free radical scavenging medicaments, platelet aggregation inhibitors, anti-inflammatory medicaments and antioxidant medicaments, and can prevent and treat nerve injury, degenerative diseases and ischemic diseases.

The method for synthesizing the benzo-cyclopentenone derivative is simple, and the raw materials are cheap and easy to obtain, so that the benzo-cyclopentenone derivative is suitable for industrial application.

Drawings

FIG. 1: rat MCAO model pharmacodynamics experiment shows the cerebral infarction of rat.

Detailed Description

Definition of

In the present invention, the term "halogen" means fluorine, chlorine, bromine and iodine.

In the present invention, the term "alkyl" used either alone or as part of a substituent group includes straight and branched chains, and the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 4 carbon atoms. Examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, but are not limited thereto.

In the present invention, the term "cycloalkyl" used either alone or as part of a substituent group means a cyclic saturated hydrocarbon group, the cycloalkyl group preferably having 3 to 12 carbon atoms, more preferably having 3 to 8 carbon atoms, and further preferably having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, but are not limited thereto.

In the present invention, the term "aryl" denotes a carbocyclic aryl or biaryl. Carbocyclic aryl is an aromatic cyclic hydrocarbon containing 6 to 18 carbon atoms, preferably 6 to 14, more preferably 6 to 10 carbon atoms, which may be monocyclic, bicyclic or tricyclic. Biaryl is a group formed by two or more carbocyclic aryl groups joined together. Examples of aryl groups include, for example, phenyl, naphthyl, and the like, but are not limited thereto.

In the present invention, the term "heterocycloalkyl group" means a saturated cyclic group containing 1 to 4, preferably 1, 2,3 or 4 hetero atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, a silicon atom, and 5 to 14, preferably 5 to 10, more preferably 5 to 8 ring atoms which may form an oxide when they are nitrogen atoms, sulfur atoms or phosphorus atoms. Examples of heterocycloalkyl include, for example, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, and the like, but are not limited thereto.

In the present invention, the term "heteroaryl group" means an aromatic ring group containing 1 to 4, preferably 1, 2,3 or 4 hetero atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, a silicon atom, and 5 to 14, preferably 5 to 10, more preferably 5 to 8 ring atoms which may form an oxide when they are nitrogen atoms, sulfur atoms or phosphorus atoms, or a benzene-fused ring group thereof. Examples of heteroaryl groups include, for example, pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, and the like, but are not limited thereto.

In the present invention, the term "alkylene" means a group remaining after one hydrogen is removed from an alkyl group, and includes straight chain and branched chain either alone or as part of a substituent, the alkylene group preferably having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 4 carbon atoms, and examples of the alkylene group include, for example, -CH₂-、-C(CH₃)₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CH(CH₃)-、-CH₂CH(CH₃)CH₂-、-CH₂CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂CH₂CH₂-and the like, but not limited thereto.

In the present invention, the term "Pharmaceutically acceptable salts" is described in Berge, et a1., "pharmaceutical acceptable salts", j.pharm.sci., 66, 1-19(1977), which salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with an acid, for example: hydrochloride, hydrobromide, sulphate, pyrosulphate, hydrogen sulphate, sulphite, bisulphite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, citric acid, maleic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, mandelate, pyruvate, stearate, ascorbate, salicylate. When the compound of the present invention contains an acidic group, pharmaceutically acceptable salts thereof may further include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; examples of the organic base salt include salts with ammonia, alkylamines, hydroxyalkylamines, amino acids, and N-methylglucamine.

In the present invention, the term "prodrug" refers to a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.

In the present invention, the term "solvate" refers to a combination or complex of a compound with one or more solvent molecules. Examples of the solvate-forming solvent include, but are not limited to, water (also referred to as hydrate at this time), ethanol, methanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, and the like, but are not limited thereto.

In the present invention, the compounds of the present invention may exist in the form of isomers and mixtures thereof; such as tautomers, optical isomers, enantiomers, diastereomers. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers or diastereomers and mixtures thereof, for example as racemates. The compounds of the invention may exist in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration at a particular position of the compound.

In a first aspect the present invention provides a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof:

wherein:

x is selected from-O-, -NR₄-、-CR₅R₆-any of;

R₀、R₁each independently selected from any one of hydrogen, C1-C10 alkyl, C3-C12 cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

R₂selected from hydrogen, halogen, hydroxy, C1-6 alkoxy, nitro, -ONO₂Any one of the above;

l is selected from C1-C10 alkylene optionally substituted with one or more groups selected from halogen, hydroxy, nitro, amino;

R₃each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C6-C14 aryl;

m is selected from 0,1, 2 or 3, and when m is 2 or 3, each R₃May be the same or different;

R₄selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl;

R₅、R₆each independently selected from hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or R₅、R₆Together with the carbon atom to which they are attached form a C3-8 cycloalkyl group;

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alone or as part of any group, is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C3-C8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-2 alkylC 6-C10 aryl, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

Preferably, the benzocyclopentenone derivative of formula I has a structure represented by the following formula I-1 or a structure represented by the formula I-2:

preferably, X is selected from-O-or-CR₅R₆-。

More preferably, X is selected from-O-or-CH₂-。

Preferably, said R is₀Is selected from any one of hydrogen, halogen and C1-C4 alkyl.

Preferably, said R is₁Any one selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alone or as part of any group, optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C3-C8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-2 alkylC 6-C10 aryl, C1-6 alkoxycarbonyl, and C1-6 alkylcarbonyl.

More preferably, R is₁Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,

Morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothienyl, phenyl, naphthyl, benzyl, pyrrolyl, pyrazolyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, wherein said morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothienyl, phenyl, naphthyl, benzyl, pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinylThe quinolinyl is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C4 alkyl, C1-4 alkoxy, C1-4 alkylamino, benzyl, C1-4 alkoxycarbonyl, or C1-4 alkylcarbonyl; r₇Any one selected from hydrogen, C1-4 alkyl, -C1-2 alkyl C6-C10 aryl, C1-6 alkoxycarbonyl, C6-C10 aryl C1-2 alkylcarbonyl; r₁₁Is selected from N or CH; l is₁Is selected from C₁-C₄An alkylene group; a. each b is independently selected from 0,1 or 2.

More preferably, R is₁Selected from ethyl, n-propyl, n-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Any one of pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, which pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C4 alkyl, C1-4 alkoxy, C1-4 alkylamino; r₁₁Is selected from CH; r₇Any one selected from benzyl and C1-4 alkoxycarbonyl; l is₁Is selected from-CH₂-、-C(CH₃)₂-、-CH₂CH₂-; a. each b is independently selected from 0,1 or 2. Preferably, said R is₇Is selected from any one of benzyl and tert-butyloxycarbonyl.

Preferably, said R is₁Selected from:

preferably, said R is₂Selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-4 alkoxy, nitro, -ONO₂Any one of them.

More preferably, R is₂Selected from fluorine, hydroxyl, methoxy, ethoxy, -ONO₂Any one of them.

Preferably, L is selected from C2-C6 alkylene, optionally substituted with one or more groups selected from halogen, hydroxy.

More preferably, L is selected from- (CH)₂)_nN is selected from 2,3, 4,5 or 6.

Preferably, said R is₃Each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4 alkylamino, phenyl, said alkyl, cycloalkyl, phenyl, alone or as part of any group, optionally substituted with one or more groups selected from halogen, hydroxy, C1-C4 alkyl, C1-4 alkoxy.

Preferably, said R is₃Each independently selected from any one of hydrogen, halogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy and phenyl.

Preferably, said R is₄Any one selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl and cyclohexyl.

Preferably, said R is₅、R₆Each independently selected from any one of hydrogen, halogen, methyl, ethyl, isopropyl, tertiary butyl, cyclopropyl, cyclopentyl and cyclohexyl, or R₅、R₆Together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Preferably, the benzocyclopentenone derivative of formula I is selected from:

the present invention provides a pharmaceutical composition comprising at least one benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof. The pharmaceutical composition may comprise a pharmaceutically acceptable excipient.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity. Suitable excipients are well known to those skilled in the art and include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. One skilled in the art will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many of the excipient is present in the formulation and those other excipients are present in the formulation.

The pharmaceutical composition may be formulated into various types of administration unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions) and the like, depending on the purpose of treatment. Furthermore, it may be provided in the form of liposomes, micelles, microspheres or nanosystems.

For shaping the pharmaceutical composition in the form of tablets, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. Optionally, conventional coating materials can be selected to make into sugar-coated tablet, gelatin film-coated tablet, enteric coated tablet, film-coated tablet, double-layer film tablet and multilayer tablet.

For shaping the pharmaceutical composition in the form of pellets, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. For an individual of about 50-70kg, the disclosed pharmaceutical compositions may be in unit dosage form containing about 1-1000mg, or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition will depend on the species, weight, age and condition of the individual, the disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disease. In one embodiment, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg.

The compound has excellent protective effect on cerebral cortex neuron cells, particularly under the condition of oxygen deficiency and sugar deficiency. Therefore, the compound of the present invention can be used for preparing neuroprotective agents, platelet aggregation inhibitors, free radical scavenging drugs, vasodilators or antioxidant drugs. The compound can prevent and treat neurodegenerative diseases, such as senile dementia, Parkinson and the like; can be used for preventing and treating ischemic diseases such as myocardial ischemia and apoplexy. Furthermore, the compounds of the invention can be used in connection with the treatment of stroke in the convalescent phase.

Accordingly, the present invention provides the use of a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof, for the preparation of a neuroprotective agent, a platelet aggregation inhibitor, a free radical scavenging drug, a vasodilator or an antioxidant drug.

The present invention also provides the use of the benzocyclopentenone derivatives of formula I, or pharmaceutically acceptable salts, prodrugs, solvates and stereoisomers thereof, for the preparation of a medicament for the prevention and treatment of neurodegenerative diseases or ischemic diseases. Preferably, the neurodegenerative diseases comprise senile dementia, Parkinson and the like; the ischemic diseases include myocardial ischemia and cerebral apoplexy.

The invention also provides the application of the benzo-cyclopentenone derivative shown in the formula I or pharmaceutically acceptable salts, prodrugs, solvates and stereoisomers thereof in preparing medicaments for preventing and treating myocardial ischemia and cerebral apoplexy or treating related diseases in the rehabilitation period of the cerebral apoplexy.

The present invention provides a process for the preparation of a benzocyclopentenone derivative of formula I, said process comprising the steps of:

reacting the compound of formula II with the compound of formula III under the action of alkali to generate a compound of formula IV; thereafter, reacting the compound of formula IV with a compound of formula V, optionally in the presence of a catalyst, to produce a compound of formula I;

wherein, X, R₀-R₃L, m are as defined herein; the M is selected from chlorine or bromine, preferably bromine.

Preferably, the base is selected from an inorganic base or an organic base; the inorganic base includes sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; the organic base includes triethylamine, pyridine, etc.

The optional catalyst includes, but is not limited to, metal oxides (e.g., alumina), zeolites, molecular sieves, acids (e.g., formic acid), and the like.

The above reaction may be carried out in an organic solvent, which may be a solvent inert to the reaction commonly used in the art. For example, there may be mentioned alcohols such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane, chloroform, ethers such as diethyl ether, methyl ethyl ether, esters such as ethyl acetate, formic acid acetic acid, hydrocarbons such as n-hexane, cyclohexane, benzene, toluene, xylene, acetonitrile, DMF, DMSO and the like, but not limited thereto.

Hereinafter, preferred examples of the invention will be described in detail. The examples are given for the purpose of better understanding the inventive content and are not intended to be limiting. Insubstantial modifications and adaptations of the embodiments in accordance with the present disclosure remain within the scope of the invention.

The experimental procedures in the following examples are conventional unless otherwise specified. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications.

Example 1:

preparation of 6- (2-hydroxyethoxy) benzofuran 3(2H) -one:

6-hydroxybenzofuran-3 (2H) -one (1.4g, 9.3mmol) was added to the reaction flask, 20mL of DMF was added and stirred to dissolve it, then 2-bromoethanol (6.6mL, 93mmol) and potassium carbonate (3.2g, 23mmol) were added in that order and reacted at 50 ℃ overnight. After completion of the reaction, the reaction mixture was directly filtered by suction, extracted with ethyl acetate (3X 50mL), and the organic phases were combined, washed with 3% dilute hydrochloric acid (100mL), saturated sodium bicarbonate (100mL) and saturated brine (100mL) in this order 1 time each, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to give 1.53g of a white solid in 85% reaction yield.

¹H NMR (600MHz, chloroform-d) δ 7.52(d, J ═ 8.5Hz,1H),6.66(dd, J ═ 8.6,2.1Hz,1H),6.44(d, J ═ 2.1Hz,1H),5.03(s.2h), 4.11-4.03 (m,2H), 3.97-3.82 (m,2H).

MS-ESI:[M+H]+:195.1。

(E) Preparation of-2-butenyl-6- (2-hydroxyethoxy) benzofuran-3- (2H) -one (Compound 7):

6- (2-hydroxyethoxy) benzofuran 3(2H) -one (0.07g, 0.36mmol) was charged into a reaction flask, 6mL of methylene chloride was added thereto, and the mixture was dissolved by stirring, followed by addition of n-butyraldehyde (0.08mL, 1.1mmol) and alumina (1.4g) in this order and reaction at room temperature for 30 min. After completion of the reaction, the reaction mixture was filtered with suction and washed with dichloromethane (50 mL). The solvent was removed by rotary evaporation to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give 76mg of a pale yellow oil with a reaction yield of 85%.

¹H NMR (600MHz, chloroform-d) δ 7.67(d, J ═ 8.5Hz,1H),6.74(dd, J ═ 8.6,2.1Hz,1H),6.68(d, J ═ 2.1Hz,1H),6.13(t, J ═ 7.9Hz,1H), 4.20-4.18 (m,2H), 4.13-3.94 (m,2H), 2.49-2.29 (m,2H), 1.62-1.56 (m,2H),1.01(t, J ═ 7.4Hz,3H).

¹³C NMR (150MHz, chloroform-d) delta 182.20,168.45,166.42,149.89,125.97,116.29,115.88,112.04,96.96,69.99,61.09,27.67,21.98, 13.90.

HRMS-ESI [ M + H ] + M/z theoretical value: C14H16O4,248.1049, respectively; found 249.1121.

The following compounds were synthesized with reference to the above procedure:

compound 1:

¹h NMR (600MHz, chloroform-d) δ 7.70(d, J ═ 8.6Hz,1H),6.73(dd, J ═ 8.6,2.2Hz,1H),6.66(d, J ═ 2.1Hz,1H),6.14(t, J ═ 7.9Hz,1H), 4.92-4.84 (m,2H), 4.41-4.31 (m,2H),2.43(q, J ═ 7.6Hz,2H), 1.61-1.55 (m,2H),1.02(t, J ═ 7.4Hz,3H).

¹³C NMR (150MHz, chloroform-d) delta 182.10,168.26,165.39,149.81,126.14,116.51,116.39,111.72,97.12,70.29,64.60,27.68,21.96,13.89.

HRMS-ESI[M+H]⁺Theoretical value of m/z: C14H15NO6,293.0899, respectively; measured value: 294.0978.

compound 2:

¹h NMR (600MHz, chloroform-d) δ 7.71(d, J ═ 8.6Hz,1H),6.74(dd, J ═ 8.6,2.2Hz,1H),6.68(d, J ═ 2.1Hz,1H),5.65(d, J ═ 10.9Hz,1H), 5.03-4.80 (m,2H), 4.40-4.32 (m,2H), 2.04-1.98 (m,1H), 1.17-1.08 (m,2H), 0.83-0.77 (m,2H).

¹³C NMR (150MHz, chloroform-d) delta 181.16,167.91,165.17,149.71,126.09,122.72,116.50,111.65,97.10,70.33,64.59,9.76,9.49(x 2).

HRMS-ESI[M+H]⁺Theoretical value of m/z: C14H13NO6,291.0743, respectively; measured value: 292.0820.

compound 3:

¹h NMR (600MHz, chloroform-d) δ 7.70(d, J ═ 8.5Hz,1H),6.74(dd, J ═ 8.6,2.1Hz,1H),6.66(d, J ═ 2.1Hz,1H),5.97(d, J ═ 9.3Hz,1H), 4.95-4.76 (m,2H)),4.45–4.27(m,2H),4.13(s,2H),2.89–2.83(m,3H),1.80(d,J＝13.1Hz,2H),1.65(s,2H),1.49(s,9H)。

¹³C NMR (150MHz, chloroform-d) delta 182.29,168.26,165.56,154.82,148.73,126.23,118.58,116.14,111.84,97.20,79.64,70.26,64.66,43.63,43.00,33.58,31.02,28.47(x3), 25.18.

Compound 4:

¹h NMR (600MHz, chloroform-d) δ 7.75(dd, J ═ 8.3,1.8Hz,1H),6.99(d, J ═ 1.8Hz,1H), 6.82-6.75 (m,2H),4.90-4.88(m,2H), 4.38-4.36 (m,2H),2.68(s,3H),2.64(s,3H),2.58(s, 3H).

Compound 5:

¹h NMR (600MHz, chloroform-d) δ 7.70(d, J ═ 8.5Hz,1H), 7.38-7.31 (m,5H),6.74(dt, J ═ 8.5,1.5Hz,1H),6.66(d, J ═ 2.1Hz,1H),6.02(d, J ═ 9.4Hz,1H), 5.02-4.79 (m,2H), 4.54-4.18 (m,2H),3.56(s,2H),2.94(d, J ═ 11.2Hz,2H),2.72(dd, J ═ 13.5,7.5Hz,1H),2.14(t, J ═ 11.3Hz,2H), 1.85-1.76 (m,2H), 1.67-1.61 (m,2H).

Compound 6:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 8.6Hz,1H), 7.46-7.40 (m,2H),7.35(t, J ═ 7.6Hz,2H),7.27(d, J ═ 7.3Hz,1H),6.73(dd, J ═ 8.6,2.2Hz,1H),6.68(d, J ═ 2.1Hz,1H),5.99(d, J ═ 9.4Hz,1H), 4.94-4.77 (m,2H), 4.45-4.26 (m,2H),3.61(s,2H),3.28(t, J ═ 3.5Hz,2 ddh), 3.09 (p, J ═ 11.6,9.3,5.7, 1H),2.17 (t, 2H), 10.17 (m,2H), 1.5H, 9.5H, 1H, 9.72H, 1H, 9.9, 1H, 5 ddh, 3.72 (d, 2H).

Compound 8:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 9.2Hz,1H),6.77(d, J ═ 8.6Hz,1H),6.69(s,1H),5.96(d, J ═ 9.3Hz,1H),4.20(t, J ═ 4.5Hz,2H),4.14(q, J ═ 6.9Hz,2H),4.05(t, J ═ 4.6Hz,2H),2.89-2.84(m,3H),1.81(d, J ═ 13.2Hz,2H),1.64(s,2H),1.50(s, 9H).

Compound 9:

¹h NMR (600MHz, chloroform-d) δ 7.68(d, J ═ 8.5Hz,1H), 6.78-6.72 (m,1H),6.69(s,1H),5.64(d, J ═ 10.8Hz,1H),4.19(d, J ═ 4.5Hz,2H),4.04(d, J ═ 5.0Hz,2H),2.00(dtt, J ═ 12.9,9.0,4.5Hz,1H),1.12(dt, J ═ 7.4,3.7Hz,2H),0.79(dt, J ═ 7.1,3.3Hz, 2H).

¹³C NMR (151MHz, chloroform-d) delta 181.31,168.11,166.27,149.78,125.91,122.59,115.90,112.02,96.93,70.01,64.57,61.03,9.74,9.45(x2).

HRMS-ESI[M+H]⁺Theoretical value of m/z: C14H14O4,246.0892, respectively; measured value: 247.0966.

compound 10:

¹h NMR (600MHz, chloroform-d) δ 7.67(d, J ═ 8.5Hz,1H),7.43(d, J ═ 7.2Hz,2H),7.35(dd, J ═ 8.3,6.8Hz,2H),7.29(m,1H),6.74(dd, J ═ 8.6,2.1Hz,1H),6.69(d, J ═ 2.1Hz,1H),5.97(d, J ═ 9.4Hz,1H), 4.23-4.16 (m,2H),4.04(dd, J ═ 5.1,3.8Hz,2H),3.65(s,2H), 3.40-3.24 (m,2H),3.09(dtd, J ═ 15.1,11.6,5.7, 2H), 3.9.9, 7, 1H), 3.9.4, 5H, 1H), 3.6, 7.6, 1H), 3.6, 1H, and 1H.

Compound 11:

¹h NMR (600MHz, chloroform-d) δ 7.72(dt, J ═ 8.5,1.6Hz,1H),6.97(s,1H), 6.85-6.80 (m,1H), 6.80-6.77 (m,1H),4.21(t, J ═ 4.3Hz,2H),4.05(dt, J ═ 8.0,4.1Hz,2H),2.67(s,3H),2.64(s,3H),2.57(s,3H),2.29(ds, 1H).

Compound 12:

¹h NMR (600MHz, chloroform-d) δ 7.68(d, J ═ 8.5Hz,1H), 7.40-7.32 (m,5H),6.75(dd, J ═ 8.6,2.1Hz,1H),6.67(d, J ═ 2.1Hz,1H),6.01(d, J ═ 9.5Hz,1H),4.19(dd, J ═ 5.1,3.9Hz,2H),4.04(dd, J ═ 5.1,3.9Hz,2H),3.56(s,2H), 3.01-

2.88(m,2H),2.72(ddt,J＝14.7,10.7,5.5Hz,1H),2.20–2.10(m,2H),1.86–

1.77(m,2H),1.66(dtd,J＝13.1,11.3,3.8Hz,2H)。

Compound 13:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 8.6Hz,1H),6.72(dd, J ═ 8.5,2.1Hz,1H),6.67(d, J ═ 2.1Hz,1H),5.64(d, J ═ 10.8Hz,1H),4.71(t, J ═ 6.2Hz,2H),4.18(t, J ═ 5.9Hz,2H),2.30(p, J ═ 6.1Hz,2H), 2.05-1.93 (m,1H), 1.18-1.06 (m,2H), 0.85-0.75 (m,2H).

¹³C NMR (151MHz, chloroform-d) delta 181.20,168.08,165.84,149.78,125.96,122.39,116.10,111.82,96.88,69.51,64.33,26.82,9.70,9.42(x 2).

HRMS-ESI[M+H]⁺Theoretical value of m/z: C15H15NO6,305.0899, respectively; measured value: 306.0976.

compound 14:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 8.6Hz,1H),6.73(dd, J ═ 8.6,2.1Hz,1H),6.66(d, J ═ 2.1Hz,1H),5.96(d, J ═ 9.3Hz,1H),4.71(t, J ═ 6.1Hz,2H),4.19(t, J ═ 5.9Hz,2H),4.14(s,2H), 3.03-2.79 (m,3H),2.30(p, J ═ 6.0Hz,2H),1.80(d, J ═ 13.1Hz,2H),1.50(s, 11H).

¹³C NMR (150MHz, chloroform-d) delta 182.32,168.43,166.23,154.82,148.80,126.08,118.33,115.73,112.03,96.95,79.62,69.44,64.41,43.66,43.02,33.56,31.04,28.47(x3),26.79, 22.71.

Compound 15:

¹h NMR (600MHz, chloroform-d) δ 7.74(dd, J ═ 8.6,1.5Hz,1H),6.99(s,1H),6.80(s,1H),6.77(d, J ═ 8.6Hz,1H),4.79 to 4.53(m,2H),4.20(t, J ═ 5.9Hz,2H),2.68(s,3H),2.64(s,3H),2.58(s,3H),2.31(p, J ═ 6.0Hz, 2H).

Compound 16:

¹h NMR (600MHz, chloroform-d) δ 7.68(d, J ═ 8.6Hz,1H),7.42(d, J ═ 7.1Hz,2H),7.35(t, J ═ 7.6Hz,2H),7.26(d, J ═ 7.3Hz,1H),6.72(dd, J ═ 8.5,2.1Hz,1H),6.67(d, J ═ 2.1Hz,1H),5.98(d, J ═ 9.4, 1H),4.71(t, J ═ 6.2Hz,2H),4.18(t, J ═ 5.9Hz,2H),3.60(s,2H), 3.40-3.20 (m,2H),3.09(d, J ═ 15.2, 11.5, 7.5, 2H),3.60(s,2H), 3.40-3.20 (m,2H),3.09(d, J ═ 15.2,11.6, 7.5, 1.6, 2H), 3.3.3.73 (t, 1H), 1.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3, 3.3.3.3, 3, 3.3, 3, 1H).

Compound 17:

¹h NMR (600MHz, chloroform-d) delta 7.67(dd,J＝8.6,1.0Hz,1H),6.72(d,J＝8.5Hz,1H),6.68(s,1H),6.11(t,J＝7.7Hz,1H),4.23(t,J＝6.1Hz,2H),3.90(t,J＝6.0Hz,2H),2.43(q,J＝7.3Hz,2H),2.11(p,J＝6.0Hz,2H),1.59(m,2H),1.02(td,J＝7.4,1.0Hz,3H)。

¹³C NMR (150MHz, chloroform-d) delta 182.19,168.55,166.70,149.95,125.86,116.02,115.61,112.13,96.79,65.93,59.61,31.73,27.66,21.99, 13.90.

HRMS-ESI[M+H]⁺Theoretical value of m/z: C15H18O4,262.1205, respectively; measured value: 263.1273.

compound 18:

¹h NMR (600MHz, chloroform-d) δ 7.64(dd, J ═ 8.7,3.6Hz,1H),6.70(dt, J ═ 9.0,2.8Hz,1H),6.67(t, J ═ 2.8Hz,1H),5.63 to 5.39(m,1H),4.21(q, J ═ 5.5,5.1Hz,2H),4.05 to 3.73(m,2H),2.10(q, J ═ 5.8Hz,2H),2.02 to 1.96(m,1H),1.11(dt, J ═ 6.9,3.5Hz,2H),0.78(dt, J ═ 6.9,3.3Hz, 2H).

¹³C NMR (150MHz, chloroform-d) delta 181.30,168.21,166.54,149.83,125.79,122.30,115.61,112.10,96.73,65.86,59.46,31.77,9.71,9.42(x 2).

HRMS-ESI[M+H]⁺Theoretical value of m/z: C15H16O4,260.1049, respectively; measured value: 261.1122.

compound 19:

¹h NMR (600MHz, chloroform-d) δ 7.67(dd, J ═ 8.5,1.1Hz,1H),6.74(dt, J ═ 8.6,1.6Hz,1H),6.68(t, J ═ 1.5Hz,1H),5.94(dd, J ═ 9.3,1.1Hz,1H), 4.30-4.16 (m,2H),4.14(d, J ═ 7.0Hz,2H),3.90(t, J ═ 6.0Hz,2H), 2.99-2.72 (m,3H), 2.21-2.06 (m,2H),1.80(d, J ═ 13.3Hz,2H),1.50(s,9H),1.49(m, 2H).

Compound 20:

¹h NMR (600MHz, chloroform-d) δ 7.70(dt, J ═ 8.5,2.1Hz,1H),6.96(d, J ═ 2.1Hz,1H),6.79(d, J ═ 2.4Hz,1H),6.75(dd, J ═ 8.5,2.2Hz,1H),4.29 to 4.17(m,2H),3.88(d, J ═ 6.4Hz,2H),2.66(s,3H),2.63(s,3H),2.56(s,3H),2.10(dd, J ═ 8.9,3.3Hz, 2H).

Compound 21:

¹h NMR (600MHz, chloroform-d) δ 7.66(d, J ═ 8.6Hz,1H),7.42(d, J ═ 7.4Hz,2H), 7.38-7.32 (m,2H),7.27(t, J ═ 6.6Hz,1H),6.72(dd, J ═ 8.5,2.1Hz,1H),6.69(d, J ═ 2.1Hz,1H),5.97(d, J ═ 9.4Hz,1H),4.23(t, J ═ 6.1Hz,2H),3.90(t, J ═ 6.0Hz,2H),3.61(s,2H),3.28(s,2H), 3.16-3.00 (m,1H),2.12(q, J ═ 6.0Hz,2H),3.61(s,2H), 3.12 (q, J ═ 5.8, 1H), 1.76(t, 1H), 1H, 59(m, 1H).

Compound 22:

¹h NMR (600MHz, chloroform-d) δ 7.68(d, J ═ 8.6Hz,1H),6.71(dd, J ═ 8.6,2.1Hz,1H),6.66(d, J ═ 2.1Hz,1H),5.63(d, J ═ 10.8Hz,1H), 4.63-4.44 (m,2H), 4.22-3.94 (m,2H), 2.06-2.00 (m,1H),1.99(p, J ═ 2.8Hz,4H), 1.17-1.05 (m,2H), 0.87-0.75 (m,2H).

¹³C NMR (150MHz, chloroform-d) delta 181.23,168.16,166.25,149.80,125.90,122.27,115.84,111.94,96.74,72.69,67.75,25.39,23.79,9.70,9.41(x 2).

HRMS-ESI[M+H]⁺Theoretical value of m/z: C16H17NO6,319.1056, respectively; measured value: 320.1124.

compound 23:

¹h NMR (600MHz, chloroform-d) δ 7.73(d, J ═ 8.5Hz,1H),6.98(s,1H),6.78(d, J ═ 2.1Hz,1H),6.76(dd, J ═ 8.5,2.1Hz,1H), 4.69-4.42 (m,2H),4.13(q, J ═ 4.9,4.1Hz,2H),2.68(s,3H),2.64(s,3H),2.58(s,3H),1.99(t, J ═ 3.2Hz, 4H).

Compound 24:

¹h NMR (600MHz, chloroform-d) δ 7.70(d, J ═ 8.5Hz,1H),6.75(dd, J ═ 8.6,2.1Hz,1H),6.68(d, J ═ 2.2Hz,1H),6.13(t, J ═ 7.9Hz,1H),4.34(t, J ═ 5.8Hz,2H),3.88(t, J ═ 5.8Hz,2H),2.43(q, J ═ 7.6Hz,2H), 1.76-1.49 (m,2H),1.02(t, J ═ 7.4Hz,3H).

¹³C NMR (151MHz, chloroform-d) delta 182.13,168.35,165.78,149.87,126.06,116.31,116.18,111.91,97.13,68.49,41.33,27.67,21.97, 13.88.

Compound 25:

¹h NMR (600MHz, chloroform-d) δ 7.70(d, J ═ 8.6Hz,1H),6.76(dd, J ═ 8.6,2.1Hz,1H),6.70(d, J ═ 2.1Hz,1H),5.65(d, J ═ 10.8Hz,1H),4.34(t, J ═ 5.8Hz,2H),3.88(t, J ═ 5.8Hz,2H),2.01(dtt, J ═ 10.8,8.1,4.6Hz,1H), 1.18-1.08 (m,2H), 0.83-0.76 (m,2H).

¹³C NMR (151MHz, chloroform-d) delta 181.20,168.01,165.56,149.76,126.03,122.50,116.29,111.84,97.12,68.48,41.35,9.72,9.44(x 2).

Compound 26:

¹h NMR (600MHz, chloroform-d) δ 7.75(d, J ═ 9.1Hz,1H),6.99(s,1H), 6.85-6.78 (m,2H),4.36(t, J ═ 5.8Hz,2H),3.89(t, J ═ 5.8Hz,2H),2..68(s,3H),2.65(s,3H),2.58(s,3H)。

Compound 27:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 8.6Hz,1H),7.42(d, J ═ 7.5Hz,2H),7.35(t, J ═ 7.6Hz,2H),7.26(d, J ═ 7.4Hz,1H),6.75(dd, J ═ 8.5,2.1Hz,1H),6.69(d, J ═ 2.1Hz,1H),5.98(d, J ═ 9.4, 1H),4.34(t, J ═ 5.8Hz,2H),3.88(t, J ═ 5.8Hz,2H),3.60(s,2H),3.28(s,2H), 3.18-3.00 (m,1H), 2.16-2.h), 3.1H (m, 7.7H), 7.7.6H (d, 1H).

Compound 28:

¹h NMR (600MHz, chloroform-d) δ 7.69(d, J ═ 8.5Hz,1H), 7.38-7.32 (m,4H),7.28(td, J ═ 5.7,5.3,2.9Hz,1H),6.75(dd, J ═ 8.6,2.1Hz,1H),6.67(d, J ═ 2.2Hz,1H),6.01(d, J ═ 9.4Hz,1H),4.33(t, J ═ 5.8Hz,2H),3.87(t, J ═ 5.7Hz,2H),3.55(s,2H),2.93(dd, J ═ 9.4,5.8Hz,2H),2.73(td, J ═ 15.4,9.4,4, 4.0, 1.0, 2.17, 2.85H), 1.71H (1H), 1.71H), 1H, and 1H.

Compound 29:

¹HNMR (600MHz, chloroform-d) δ 7.43(d, J ═ 8.3Hz,1H),7.32(d, J ═ 2.6Hz,1H),7.22(dd, J ═ 8.3,2.6Hz,1H),6.30(dt, J ═ 10.9,2.0Hz,1H),4.24 to 4.09(m,2H),4.01(q, J ═ 4.9Hz,2H),3.73(d, J ═ 1.9Hz,2H),2.20(t, J ═ 6.2Hz,1H),1.71 to 1.61(m,1H),1.11 to 1.05(m,2H),0.84 to 0.76(m, 2H).

Compound 30:

¹h NMR (600MHz, chloroform-d) δ 7.78(t, J ═ 2.2Hz,1H), 7.52-7.47 (m,1H),7.38(d, J ═ 2.5Hz,1H),7.27(dd, J ═ 8.4,2.7Hz,1H),4.22(d, J ═ 2.2Hz,2H),4.19(dd, J ═ 5.1,4.0Hz,2H), 4.06-3.99 (m,2H),2.72(s,3H),2.61(s,3H),2.56(s, 3H).

Compound 31:

¹HNMR (600MHz, chloroform-d) δ 7.48-7.41 (m,1H),7.29(d, J ═ 2.6Hz,1H),7.21(dd, J ═ 8.3,2.6Hz,1H),6.31(dt, J ═ 10.9,1.9Hz,1H), 4.96-4.74 (m,2H), 4.46-4.16 (m,2H),3.74(d, J ═ 1.9Hz,2H),1.68(dtt, J ═ 10.9,7.9,4.5Hz,1H), 1.14-1.05 (m,2H), 0.85-0.76 (m,2H).

Compound 32:

¹h NMR (600MHz, chloroform-d) δ 7.78(t, J ═ 2.2Hz,1H),7.51(d, J ═ 8.3Hz,1H),7.34(d, J ═ 2.5Hz,1H),7.26(dd, J ═ 8.3,2.6Hz,1H), 5.00-4.65 (m,2H), 4.44-4.30 (m,2H),4.23(d, J ═ 2.2Hz,2H),2.72(s,3H),2.61(s,3H),2.56(s, 3H).

Efficacy example 1: rat brain primary cortical neuron cell hypoxia and sugar-deficiency injury

Selecting primary cortical neuron cells of rat brain growing to about 7d to perform an in vitro oxygen-sugar deprivation/reoxygenation (OGD/R) model. Using 4X 10⁴The cell density of (2) was inoculated in a 12-well culture plate, and a blank group was prepared using 1% FBS EMEM medium 5% CO₂And performing conventional culture in an incubator at 37 ℃, and starting to prepare an OGD/R model after performing conventional culture for 24 hours by using an OGD/R model group and an administration group which respectively contain 1% FBS and a drug-containing EMEM culture medium with corresponding concentrations: the medium was first replaced with EMEM medium without glucose and serum, while the cells were plated in 5% CO₂、95％N₂Three-gas cultureCulturing in a box for 2h to complete the anoxic process; the cell culture medium was then changed to complete DMEM medium while the cells were placed in a medium containing 5% CO₂Culturing in an incubator for 24h to complete the reoxygenation process. 4h before the end of incubation, 20. mu.L of MTT solution (5mg/mL) was added to each well. After incubation is finished, discarding supernatant of each well, adding 150 mu LDMSO into each well, oscillating on a cell oscillator for 10min, and determining OD570 by using an enzyme-labeling instrument after crystals are fully dissolved. Results are expressed in mean ± SD format. Statistical differences between the data groups were determined to be significant using one-way anova and Sidak's tests, with P values less than 0.05. The formula: survival rate was (experimental OD value/control OD value) × 100%. The test results are shown in table 1 below:

table 1: effect of different Compounds on rat cortical neuronal cell survival in response to the OGD/R procedure

Note: drug treatment group vs OGD/R group<0.05,**p<0.01; compared with the edaravone group with the positive drug of the equimolar concentration,^#p<0.05，^##p<0.01; compared with the positive medicine senkyunolide I group with the equal molar concentration in the medicine treatment group,^&p<0.05，^&&p<0.01。

experimental results show that the compound can remarkably improve the survival rate of rat brain primary cortical neuron cells after OGD/R modeling, and compared with positive drugs of edaravone and senkyunolide I, part of the compound has more prominent effect of protecting brain neurons.

Example two: rat MCAO model pharmacodynamic experiment:

selecting 40 rats with proper weight, and randomly grouping the rats into four groups according to a table; before molding for 2h, all mice were dosed by intraperitoneal injection once according to the dose in the table. All rats in the operative group were anesthetized with 3% isoflurane at a flow rate of 1.5L/min, neck hair was removed with an animal shaver, sterilized with iodophor and alcohol, the skin was incised in the middle of the neck, subcutaneous tissue was bluntly isolated, the carotid artery was then looked down along the right sternocleidomastoid tendon, the arterial sheath was carefully isolated, the vagus nerve was not injured, the common, external and internal carotid arteries were subsequently isolated, the common and external carotid arteries were ligated, the internal carotid artery was occluded with an arterial clip, and a small incision was cut at the common carotid artery with an ophthalmic scissors, a prepared plug was inserted, the plug was just inserted into the anterior cerebral artery in neck, blocking the opening of the middle cerebral artery. The ligature is tied with a thread knot and the muscle and skin are sutured, and the sutured rat is placed in a cage to strengthen the heat preservation after the operation. Animals in the sham group were subjected to the same anesthesia and surgery procedure, but did not embolize the middle cerebral artery to create a cerebral ischemia model. The day of surgery is recorded as D1 days, the medicine is continuously injected into the abdominal cavity for 14 days, the medicine carrying material hydroxypropyl-beta-cyclodextrin water solution with the indicated dosage is administered to the pseudochiral group and the model group, all animals are drawn on the day 15, serum is reserved for Elisa detection, and brain tissue is reserved for pathology detection.

Table 2: grouping and dosing

4 rats were randomly selected for each group, and brain tissue was stained for TTC, the results are shown in FIG. 1. Infarct size analysis results are given in the following table:

table 3: infarct size in rats

Group of	Infarct size (percentage)	Group of	Infarct size (percentage)
				A-5	0	C-5	25.89
A-6	0	C-6	33.32
				A-7	0	C-7	25.07
A-8	0	C-8	27.53
				B-5	31.42	E-5	20.40
B-6	35.75	E-6	17.67
				B-7	23.31	E-7	14.72
B-8	31.97	E-8	13.14

As shown in table 3, compound 9 exhibited a better brain-protecting effect than the positive drug edaravone, and significantly reduced the cerebral infarction area, compared to the operative group.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (10)

1. A benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof:

wherein:

x is selected from-O-, -NR₄-、-CR₅R₆-any of;

R₀、R₁each independently selected from any one of hydrogen, C1-C10 alkyl, C3-C12 cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

R₂selected from hydrogen, halogen, hydroxy, C1-6 alkoxy, nitro, -ONO₂Any one of the above;

l is selected from C1-C10 alkylene optionally substituted with one or more groups selected from halogen, hydroxy, nitro, amino;

R₃each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxyCarbonyl, C1-6 alkylcarbonyl, C6-C14 aryl;

m is selected from 0,1, 2 or 3, and when m is 2 or 3, each R₃May be the same or different;

R₄selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl;

R₅、R₆each independently selected from hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or R₅、R₆Together with the carbon atom to which they are attached form a C3-8 cycloalkyl group;

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alone or as part of any group, is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C3-C8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-2 alkylC 6-C10 aryl, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

2. The benzo-cyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof according to claim 1, wherein the benzo-cyclopentenone derivative of formula I has a structure represented by the following formula I-1 or a structure represented by the formula I-2:

3. the benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof, according to claim 1, wherein X is selected from-O-or-CH₂-。

4. The benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof, according to claim 1, wherein R is₁Selected from any one of C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heterocycloalkyl, C6-C10 aryl and 5-10 membered heteroaryl(iii) said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alone or as part of any group, is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C3-C8 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-2 alkylC 6-C10 aryl, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

5. The benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof, according to claim 1, wherein R is₁Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,

Any one of morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothienyl, phenyl, naphthyl, benzyl, pyrrolyl, pyrazolyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, wherein said morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothienyl, phenyl, naphthyl, benzyl, pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl are optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C1-C4 alkyl, C1-4 alkoxy, C1-4 alkylamino, benzyl, C1-4 alkoxycarbonyl, or C1-4 alkylcarbonyl; r₇Any one selected from hydrogen, C1-4 alkyl, -C1-2 alkyl C6-C10 aryl, C1-6 alkoxycarbonyl, C6-C10 aryl C1-2 alkylcarbonyl; r₁₁Is selected from N or CH; l is₁Is selected from C₁-C₄An alkylene group; a. b is each independently selected from 0,1 or 2;

preferably, said R is₁Selected from:

6. the benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof, according to claim 1, wherein R is₂Selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-4 alkoxy, nitro, -ONO₂Any one of them.

7. The benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate and stereoisomer thereof, according to claim 1, characterized in that it is selected from:

8. a pharmaceutical composition comprising at least one benzocyclopentenone derivative of formula I according to any one of claims 1-7, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof.

9. Use of a benzocyclopentenone derivative of formula I, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof, according to any one of claims 1-7, for the preparation of a medicament, which is a neuroprotective agent, a platelet aggregation inhibitor, a free radical scavenging drug, a vasodilator or an antioxidant, or for the prevention and treatment of neurodegenerative or ischemic diseases, or for the treatment associated with the recovery from stroke; preferably, the neurodegenerative diseases include senile dementia and parkinson; the ischemic diseases include myocardial ischemia and cerebral apoplexy.

10. A process for the preparation of a benzocyclopentenone derivative of formula I according to claim 1, comprising the steps of:

reacting the compound of formula II with the compound of formula III under the action of alkali to generate a compound of formula IV; thereafter, reacting the compound of formula IV with a compound of formula V, optionally in the presence of a catalyst, to produce a compound of formula I;

wherein, X, R₀-R₃L, m is as defined in claim 1; and M is selected from chlorine or bromine.

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