Salt of donepezil derivative and use thereof in medicine

Abstract

The present application relates to the salt of donepezil derivative and its application in medicine, specifically, the present application relates to the salt of compound shown in formula (I), the salt of the compound can play the role of long-acting inhibition of acetylcholinesterase expression, thereby more long-acting prevention and / or treatment of Alzheimer's disease, wherein R 1 has the meaning described in the present application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically, to a salt of donepezil and a pharmaceutical composition thereof, and further to the use of a salt of donepezil or a composition of a salt of donepezil in the preparation of a medicament, particularly in the preparation of a medicament for the treatment of Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system with an insidious onset and a chronic, progressive course. It is mainly characterized by progressive memory impairment, cognitive dysfunction, personality changes, and language disorders, severely affecting social, occupational, and daily life functions. The cholinergic hypothesis posits that the pathophysiology of AD-related cognitive impairment is attributed to the destruction or loss of cholinergic neurons, leading to a decrease in acetylcholine levels and consequently, a series of pathological features including cognitive dysfunction. Acetylcholinesterase (AChE) is a highly efficient hydrolase that catalyzes the hydrolysis of acetylcholine to produce choline and acetate ions. Reversibly inhibiting acetylcholinesterase activity reduces the hydrolysis of acetylcholine, thereby increasing the acetylcholine content at receptor sites and improving symptoms.

[0003] Donepezil, an acetylcholinesterase inhibitor, is indicated for Alzheimer's disease. It has the advantages of high bioavailability, easy absorption, and low toxicity. However, after administration, the blood drug concentration increases, which can easily cause gastrointestinal side effects such as vomiting and diarrhea.

[0004] To facilitate medication use for Alzheimer's patients, reduce medication frequency, improve patient compliance, and maintain therapeutic drug concentrations over a longer period, developing long-acting sustained-release injectable formulations is a better approach to address related issues. Patent application CN109803654A proposed developing donepezil bis(hydroxynaphthyl) salt as a long-acting injectable formulation, but this project was discontinued after reaching Phase I clinical trials. Through related experiments, the inventors discovered that donepezil bis(hydroxynaphthyl) salt causes a burst release in animals during the initial injection phase, leading to excessively high blood drug concentrations and adverse reactions.

[0005] Therefore, there is a need to develop a longer-acting and safer parenteral drug. Summary of the Invention

[0006] This invention aims to at least partially address one of the technical problems existing in the prior art. This invention provides a salt of donepezil derivatives with low solubility, suitable for use as a long-acting formulation.

[0007] On one hand, the present invention relates to salts of compounds represented by formula (I),

[0008]

[0009] Among them, R 1 C 1-21 Alkyl, C 3-6 cycloalkyl or C 6-10 Aromatic ring, wherein the C 1-21 Alkyl, C 3-6 cycloalkyl and C 6-10 The aromatic rings are each independently and optionally unsubstituted or replaced by 1, 2, 3 or 4 rings selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 Alkyl and C 1-4 Substituents of alkoxy groups;

[0010] The salt is a dihydroxynaphthalate, oxalate, phosphate, p-toluenesulfonate, fumarate, or naphthalenesulfonate.

[0011] In some embodiments of the present invention, R 1 C 1-5 Alkyl, C 6-15 Alkyl, C 16-21 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, wherein the C1-C5 alkyl, C6-C5 alkyl, or C6-C5 alkyl... 15 Alkyl, C 16 -C 21 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl groups are each independently and optionally unsubstituted or substituted by 1, 2, 3, or 4 groups selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 Alkyl and C 1-4 The alkoxy group is replaced by a substituent.

[0012] In some embodiments of the present invention, R 1 The methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl groups are used, wherein the methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl groups are each optionally unsubstituted or substituted by 1, 2, 3, or 4 substituents selected from -OH, -F, -Cl, -Br, -I, =O, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, and 2-propoxy groups.

[0013] In some embodiments of the present invention, the salt of the present invention has one of the following structures:

[0014]

[0015] In all donepezil derivatives that form dihydroxynaphthol salts, the "2" below the donepezil derivative indicates that two donepezil derivative molecules and one dihydroxynaphthol acid molecule form a salt.

[0016] On the other hand, the present invention relates to a pharmaceutical composition comprising the salt described herein;

[0017] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0018] In another aspect, the present invention relates to the use of the salt, or a pharmaceutical composition thereof, in the preparation of a medicament for inhibiting acetylcholinesterase expression or for the prevention and / or treatment of Alzheimer's disease.

[0019] In some embodiments of the present invention, the dosage form of the drug is selected from injections, tablets, capsules, or granules.

[0020] Detailed Description of the Invention

[0021] This invention is intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials described herein can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0022] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0023] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0024] Definitions and general terms

[0025] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0026] In this invention, "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 20°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 25°C to 30°C.

[0027] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases “each and each is independently”, “each and each is independently”, and “each and each is independently” used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0028] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0029] As used in this invention, the term "alkyl" includes a monovalent hydrocarbon group consisting of a saturated straight-chain or branched chain of 1-20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments have an alkyl group containing 1-12 carbon atoms, others have an alkyl group containing 1-10 carbon atoms, still others have an alkyl group containing 1-8 carbon atoms, still others have an alkyl group containing 1-6 carbon atoms, still others have an alkyl group containing 1-4 carbon atoms, and still others have an alkyl group containing 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH 2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)) 2) 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)C H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0030] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3 to 12 carbon atoms; in another embodiment, it comprises 3 to 8 carbon atoms; in yet another embodiment, it comprises 3 to 7 carbon atoms; and in still other embodiments, it comprises 3 to 6 carbon atoms. Examples of cycloalkyl groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0031] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment points to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be optionally and independently substituted by one or more substituents described in this invention.

[0032] The term "pharmaceutically acceptable" as used in this invention refers to a substance that is acceptable from a toxicological point of view for pharmaceutical use and will not adversely interact with the active ingredient.

[0033] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0034] Salts of compounds represented by formula (I) of the present invention or pharmaceutical compositions thereof

[0035] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, flow aid or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0036] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0037] The cocrystals or pharmaceutical compositions of the compounds described in this invention can be administered in any of the following manner: oral administration, inhalation spray administration, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, or intracranial injection or infusion, or via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0038] The cocrystal of the compounds described in this invention, or those containing pharmaceutically acceptable compositions, can be administered in unit doses. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0039] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0040] Oral liquids can be formulated as suspensions, solutions, emulsions, syrups, or elixirs of water and oil, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous carriers (which may contain edible oils such as almond oil), oils such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0041] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0042] For external administration, liquid dosage forms are typically made from a compound and a sterilized carrier. Water is the preferred carrier. Depending on the chosen carrier and drug concentration, the compound can be either dissolved in the carrier or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0043] When applied topically to the skin, the compounds of the present invention or their cocrystals can be formulated into suitable ointments, lotions, or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax, and water. Carriers that can be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0044] Generally, it has been proven advantageous, in both human and veterinary medicine, that the total dosage of the active compound of the present invention is about 0.5 to 500 mg per 24 hours, preferably 1 to 100 mg / kg body weight, administered in multiple single doses if appropriate, to achieve the desired effect. The amount of active compound in a single dose is preferably about 1 to 80 mg, more preferably 1 to 50 mg / kg body weight, but may not follow the above dosages, depending on the type and weight of the patient, the nature and severity of the disease, the type of formulation and the route of administration, and the dosing cycle or time interval.

[0045] Use of salts or pharmaceutical compositions of compounds represented by formula (I) of the present invention

[0046] The pharmaceutical compositions of this invention are characterized by comprising a salt of a compound of formula (I), a salt of a compound of formula (I), and pharmaceutically acceptable excipients. The salts of this invention, or pharmaceutical compositions thereof, are effective inhibitors of acetylcholinesterase and are suitable for the treatment of Alzheimer's disease, particularly for diseases or symptoms caused by acetylcholinesterase.

[0047] The term "effective amount," "effective therapeutic amount," or "effective dose" for the salts of the compounds described in this invention and / or pharmaceutically acceptable pharmaceutical compositions refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in this invention. The salts or pharmaceutically acceptable pharmaceutical compositions described in this invention are effective over a fairly wide dosage range. For example, the daily dose is approximately in the range of 0.1 mg to 100 mg / kg, divided into one or more administrations. According to the method of this invention, the cocrystals and / or pharmaceutical compositions can be effectively used to treat or reduce the severity of a disease at any dosage and via any route of administration. The precise amount required will vary depending on the patient's condition, which depends on age, the patient's general condition, the severity of the infection, specific factors, the route of administration, etc. The salts of the compounds described in this invention or pharmaceutical compositions can be administered in combination with one or more other therapeutic agents, as discussed in this invention. Attached Figure Description

[0048] Figure 1The mean plasma concentration-time curves of compounds (3), (5), (7) and donepezil bis(hydroxynaphthyl) salt are shown. Detailed Implementation

[0049] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0050] General preparation and detection methods

[0051] After reading the following detailed description, those skilled in the art will more readily understand the features and advantages of the present invention. It should be understood that, for clarity, certain features of the invention described above and below in the context of individual embodiments may also be combined to form a single embodiment. Conversely, for brevity, different features of the invention described in the context of a single embodiment may also be combined to form sub-combinations thereof. The invention disclosure is further illustrated by the following embodiments, but these embodiments should not be construed as limiting the scope of the invention or restricting it to the specific steps described herein.

[0052] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise stated. Unless otherwise stated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and were not further purified before use. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0053] The eutectic prepared in this invention was identified according to the following method:

[0054] The X-ray powder diffraction (PXRD) analysis method used in the invention is: a PANalytical diffractometer, and the radiation source used is (Cu, kα, ... 1.540598; 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage was set at 45KV and the current at 40mA. The powdered sample was prepared into a thin layer on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0168° steps within the range of 3°–40°. Data was collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0055] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: Differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a specially designed aluminum crucible with a lid, and sample analysis is performed using a linear heating device at 10 °C / min, from room temperature to approximately 300 °C. During use, the DSC chamber is purged with dry nitrogen at 50 mL / min. Plots are generated with the endothermic peak pointing downwards, and the data are analyzed and visualized using TA Universal Analysis.

[0056] The thermogravimetric analysis (TGA) method used in this invention is as follows: TGA is performed using a TA Q500 module equipped with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of sample is accurately weighed into a platinum sample pan, and sample analysis is performed using a linear heating device at 10 °C / min, from room temperature to approximately 300 °C. During use, the TGA furnace chamber is purged with dry nitrogen.

[0057] The solubility of this invention was determined using an Aglient 1200 high-performance liquid chromatograph with a VWD detector. The chromatographic column was a Waters Xbridge-C18 (4.6 × 150 mm, 5 μm). The detection wavelength was 250 nm, the flow rate was 1.0 mL / min, the column temperature was 35 °C, and the mobile phase was acetonitrile-water (v / v = 40 / 60).

[0058] Silica gel columns were used, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance (NMR) spectral data were determined using a Bruker Avance 400 NMR spectrometer or a Bruker Avance III HD 600 NMR spectrometer, with CDCl3, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are observed, the following abbreviations are used: s (single peak), s,s (single, singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), ddt (doublet of doublets), dddd (doublet of doublets), td (triplet of doublets), brs (broadened singlet). The coupling constant is expressed in Hertz (Hz).

[0059] Low-resolution mass spectrometry (MS) data were obtained using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer. Low-resolution mass spectrometry (MS) data were also obtained using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer. LC-MS was performed using high-performance liquid chromatography (manufacturer: Agilent, model: 1200) with gradient elution, scanning in positive ion mode, with a mass scan range of [missing information].

[0060] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table A.

[0061] Table A: Gradient elution conditions for mobile phase in low-resolution mass spectrometry

[0062]

[0063]

[0064] Compound purity was evaluated using Agilent 1100 series high-performance liquid chromatography (HPLC), with UV detection at 210 nm and 254 nm. Preparative chromatographic separation of compounds was achieved using Agilent 1260 series HPLC.

[0065] The following embodiments can further describe the present invention; however, these embodiments should not be construed as limiting the scope of the present invention.

[0066] In the following examples, vol indicates the amount of solvent required for 1g of raw material. For example, THF (5.00 vol) in the examples indicates that the volume of THF required for 1g of donepezil is 5mL.

[0067] The following abbreviations are used throughout this invention:

[0068] THF tetrahydrofuran EA ethyl acetate

[0069] LiHMDS (Lithium Bistrimethylsilylamine), DCM (Dichloromethane)

[0070] DMSO dimethyl sulfoxide

[0071] Example 1 Preparation of compound (1)

[0072]

[0073] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then acetic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0074] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added to 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol), and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil acetyl ester in 75% yield.

[0075] The donepezil acetate (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask and reacted at room temperature for 2 h. Then, purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, the filter cake was dried, and anhydrous ethanol (40.00 vol) was added. The mixture was then stirred at 50 °C for 1 h to obtain the target product with a purity of 95.95% and a yield of 70%.

[0076] MS(ESI,pos.ion)m / z:422.50[M+H] +

[0077] 1 H NMR (400MHz, CDCl3) δ8.50(s,2H),8.42(d,J=8.6Hz,2H),7.72(d,J=8.0Hz,2H),7.55–7.46( m,4H),7.43(d,J=4.2Hz,6H),7.31(d,J=7.4Hz,2H),7.13(t,J=7.4Hz,2H),6.94(s,2H),6.59 (s,2H),5.03(s,2H),4.23(s,4H),3.86(d,J=14.7Hz,12H),3.59(s,4H),3.24(s,4H),2.58( s,4H),2.37(d,J=6.8Hz,4H),2.26(s,6H),1.86(d,J=20.8Hz,8H),1.68(s,2H),1.28(s,2H).

[0078] Example 2 Preparation of compound (2)

[0079]

[0080] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then propionic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0081] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol), and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil propionyl ester in 68% yield.

[0082] The donepezil acetate (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask, and the mixture was reacted at room temperature for 2 h. Then, purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was dried. Anhydrous ethanol (40.00 vol) was added, and the mixture was stirred at 50 °C for 1 h to obtain the target product with a purity of 91.96% and a yield of 80%.

[0083] MS(ESI,pos.ion)m / z:436.60[M+H] +

[0084] 1 H NMR(400MHz, CDCl3)δ8.49(s,2H),8.43(d,J=8.7Hz,2H),7.72(d,J=8.0Hz,2H),7.58–7.46(m,4H) ,7.43(d,J=5.1Hz,6H),7.31(dd,J=6.9,1.5Hz,2H),7.13(t,J=7.4Hz,2H),6.94(s,2H),6.57(s,2H ),5.04(s,2H),4.23(s,4H),3.86(d,J=11.3Hz,12H),3.58(s,6H),3.24(s,4H),2.54(q,J=7.5Hz,8 H),2.36(d,J=6.9Hz,4H),1.86(d,J=21.9Hz,8H),1.68(s,2H),1.28(s,2H),1.17(t,J=7.5Hz,6H).

[0085] Example 3 Preparation of compound (3)

[0086]

[0087] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, butyric anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0088] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol), and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil butyryl ester with a yield of 72%.

[0089] The donepezilbutyroyl ester (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask, and the mixture was reacted at room temperature for 2 h. Then, purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was dried. Anhydrous ethanol (40.00 vol) was added, and the mixture was stirred at 50 °C for 1 h to obtain the target product with a purity of 99.15% and a yield of 80%.

[0090] MS(ESI,pos.ion)m / z:450.60[M+H] +

[0091] 1H NMR (400MHz, CDCl3) δ8.49(s,2H),8.44(d,J=8.7Hz,2H),7.72(d,J=8.0Hz,2H),7.52–7.36 (m,10H),7.30(d,J=10.5Hz,2H),7.13(t,J=7.4Hz,2H),6.94(s,2H),6.57(s,2H),5.04(s,2 H),4.21(s,4H),3.86(d,J=9.7Hz,12H),3.59(s,4H),3.24(s,4H),2.52(t,J=7.3Hz,8H),2. 36(d,J=6.8Hz,4H),1.88(s,8H),1.72(q,J=7.3Hz,6H),1.28(s,2H),0.96(t,J=7.4Hz,6H).

[0092] Example 4 Preparation of compound (4)

[0093]

[0094] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, butyric anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0095] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol), and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil butyryl ester with a yield of 72%.

[0096] Donepezil butyroyl ester (1.00 eq), oxalic acid (1.00 eq), and acetone (20.00 vol) were added to a reaction flask and reacted at 50 °C for 5 h. The mixture was filtered, the filter cake was washed with acetone, and dried to obtain the target product with a yield of 86% and a purity of 99.65%.

[0097] MS(ESI,pos.ion)m / z:450.60[M+H] +

[0098] 1H NMR (400MHz, CDCl3) δ7.43(d,J=6.8Hz,3H),7.37(d,J=6.3Hz,2H),6.96(s,1H),6.57(s,1H),4.21(s,2H),3.88(d,J=3.6Hz,6H) ,3.59(s,2H),3.23(s,2H),2.62(t,J=7.4Hz,4H),2.32(d,J=6.5Hz,2H),1.98–1.67(m,6H),1.63(s,1H),1.10(t,J=7.4Hz,3H).

[0099] Example 5 Preparation of compound (5)

[0100]

[0101] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, butyric anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0102] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil butyryl ester.

[0103] Donepezil butyroyl ester (1.00 eq), p-toluenesulfonic acid (1.00 eq), and ethyl acetate (10.00 vol) were added to a reaction flask, and the reaction was carried out at 50 °C for 5 h. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried to obtain the target product with a yield of 86% and a purity of 99.85%.

[0104] MS(ESI,pos.ion)m / z:450.60[M+H] +

[0105] 1H NMR (400MHz, CDCl3) δ10.83(s,1H),7.85(d,J=8.1Hz,2H),7.47(d,J=6.9Hz,2H),7.42( d,J=6.9Hz,1H),7.40–7.33(m,2H),7.22(d,J=7.9Hz,2H),6.95(s,1H),6.57(s,1H),4. 24(s,2H),3.88(s,6H),3.57(d,J=11.4Hz,2H),3.22(s,2H),2.61(t,J=7.4Hz,4H),2.3 9(s,3H),2.33(d,J=7.0Hz,2H),1.98–1.76(m,6H),1.64(s,1H),1.07(t,J=7.4Hz,3H).

[0106] Example 6 Preparation of compound (6)

[0107]

[0108] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, butyric anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0109] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil butyryl ester.

[0110] The donepezilbutyroyl ester (1.00 eq), 3-hydroxy-2-naphthoic acid (1.00 eq), and acetone (10.00 vol) obtained above were added to a reaction flask and then reacted at 50 °C for 5 h. After filtration and drying of the filter cake, the target product was obtained with a yield of 86% and a purity of 99.65%.

[0111] MS(ESI,pos.ion)m / z:450.60[M+H] +

[0112] 1H NMR (400MHz, CDCl3) δ8.58(s,1H),7.83(d,J=8.2Hz,1H),7.70(d,J=8.3Hz,1H ),7.47–7.38(m,6H),7.28(d,J=6.3Hz,2H),6.95(s,1H),6.57(s,1H),4.19(s ,2H),3.87(s,6H),3.54(s,2H),3.24(s,2H),2.54(t,J=7.3Hz,4H),2.34(d,J =6.7Hz,2H),1.87(t,J=12.9Hz,2H),1.80–1.62(m,5H),1.00(t,J=7.4Hz,3H).

[0113] Example 7 Preparation of compound (7)

[0114]

[0115] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, benzoic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0116] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0117] The donepezil benzoyl ester (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask and reacted at room temperature for 2 h. Then, purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was dried. Anhydrous ethanol (40.00 vol) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was then filtered and dried to obtain the target product with a purity of 95.86% and a yield of 80%.

[0118] MS(ESI,pos.ion)m / z:484.60[M+H] +

[0119] 1H NMR(400MHz,Chloroform-d)δ8.44(s,2H),8.37(d,J=8.7Hz,2H),7.68(d,J=8.1Hz,2H),7.6 4–7.58(m,4H),7.50–7.36(m,12H),7.32(t,J=7.8Hz,4H),7.26–7.20(m,4H),7.08(t,J=7.4H z,2H),6.87(s,2H),4.98(s,2H),4.18(d,J=2.6Hz,4H),3.96(d,J=3.6Hz,12H),3.67–3.36( m,8H),2.99(d,J=17.3Hz,3H),2.37(d,J=13.5Hz,2H),2.04(d,J=13.2Hz,3H),1.75(s,10H).

[0120] Example 8 Preparation of compound (8)

[0121]

[0122] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, benzoic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0123] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0124] The donepezil benzoyl ester (1.00 eq), oxalic acid (1.00 eq), and acetone (20.00 vol) obtained above were added to a reaction flask and then reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with acetone, and the filter cake was dried to obtain the target product with a yield of 86% and a purity of 99.65%.

[0125] MS(ESI,pos.ion)m / z:484.60[M+H] + ;

[0126] 1 H NMR (400MHz, CDCl3) δ8.22(d,J=7.4Hz,2H),7.71(t,J=7.5Hz,1H),7.58(t,J=7.4Hz,2H),7.37(dd,J=31.9,6.6Hz,5H),7.00(s, 1H),6.62(s,1H),4.17(s,2H),3.90(s,3H),3.83(s,3H),3.30(s,2H),2.95(s,4H),2.39(s,2H),1.91(s,2H),1.82–1.60(m,3H).

[0127] Example 9 Preparation of compound (9)

[0128]

[0129] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, benzoic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0130] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0131] The donepezil benzoyl ester (1.00 eq), p-toluenesulfonic acid (1.00 eq), and acetone (20.00 vol) obtained above were added to a reaction flask, and then reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with acetone, and the filter cake was dried to obtain the target product with a yield of 86% and a purity of 99.65%.

[0132] MS(ESI,pos.ion)m / z:484.60[M+H] + ;

[0133] 1H NMR (400MHz, CDCl3) δ10.51(d,J=11.5Hz,1H),7.82(d,J=8.0Hz,2H),7.58(d,J=7.4Hz, 2H),7.39(ddt,J=40.4,15.6,7.6Hz,8H),7.21(d,J=5.7Hz,2H),7.19(s,1H),6.92(s,1 H),4.20(t,J=10.4Hz,2H),3.99(d,J=20.8Hz,6H),3.48(s,2H),2.57(d,J=13.5Hz,2H) ,2.37(s,3H),2.04(d,J=13.6Hz,1H),1.87(s,4H),1.77(s,2H),1.68(d,J=12.9Hz,2H).

[0134] Example 10 Preparation of compound (10)

[0135]

[0136] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (2.00 eq) was added and the mixture was reacted at -30°C for 3 h. Then, benzoic anhydride (2.50 eq) was added, and the reaction mixture was reacted at -30°C for another 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was separated to obtain the organic phase.

[0137] The solvent was removed from the obtained organic phase under reduced pressure. The residue was then added to 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and reacted at 50 °C for 4 h. After filtration and drying of the filter cake, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was then slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0138] The donepezil benzoyl ester (1.00 eq), phosphoric acid (1.00 eq), and ethyl acetate (20.00 vol) obtained above were added to a reaction flask, and then reacted at 50 °C for 5 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with ethyl acetate, and dried to obtain the target product with a yield of 86% and a purity of 99.65%.

[0139] MS(ESI,pos.ion)m / z:484.60[M+H] + ;

[0140] 1H NMR (400MHz, CDCl3) δ7.72(d,J=7.4Hz,2H),7.46(t,J=7.4Hz,1H),7.33(t,J=7.7Hz,2H),7.30–7.24(m,5H),7.23(s,1H),6.92(s,1H),4.01(s,3H), 3.95(s,3H),3.42(s,2H),2.81–2.71(m,2H),2.26–2.10(m,4H),1.82(s,2 H),1.71(s,2H),1.57(d,J=8.7Hz,1H),1.46(d,J=9.5Hz,1H),1.32(s,4H).

[0141] Example 11 Preparation of compound (11)

[0142]

[0143] Donepezil (1.00 eq) and THF (40.00 vol) were weighed into the reaction flask, and under nitrogen protection, LiHMDS (1.500 eq) was added at -25°C. The reaction was then carried out at -30°C for 2 h. Then p-toluamide chloride (1.50 eq) was added, and the reaction flask was moved to room temperature for another 2 h. The reaction was quenched with methanol, and the mixture was evaporated to dryness. The residue was dissolved in DCM, washed with water, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EA (V / V) = 6 / 4) to obtain a white solid, donepezil p-methylbenzoyl ester.

[0144] The donepezil p-methylbenzoyl ester (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask, and the mixture was reacted at room temperature for 2 h. Purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was dried. Anhydrous ethanol (40.00 vol) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was then filtered and dried to obtain the target product with a purity of 97.18% and a yield of 86%.

[0145] MS(ESI,pos.ion)m / z:497.60[M+H] + .

[0146] Example 12 Preparation of compound (12)

[0147]

[0148] Donepezil (1.00 eq) and THF (40.00 vol) were weighed into the reaction flask, respectively. Under nitrogen protection, LiHMDS (1.500 eq) was added, and the reaction was carried out at -25°C for 2 h. Then, cyclohexyl chloride (1.50 eq) was added, and the reaction flask was moved to room temperature for 2 h. The reaction was quenched with methanol, evaporated to dryness, and the residue was dissolved in DCM. The residue was washed with water, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EA (V / V) = 6 / 4) to obtain a light orange solid, which was donepezil cyclohexyl ester.

[0149] The donepezil cyclohexyl ester (1.00 eq), dihydroxynaphthyl acid (0.50 eq), and DMSO (3.00 vol) obtained above were added to a reaction flask, and the mixture was reacted at room temperature for 2 h. Purified water (100.00 vol) was added, and stirring was continued for 0.5 h. The mixture was filtered, and the filter cake was dried. Anhydrous ethanol (40.00 vol) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was then filtered and dried to obtain the target product with a purity of 98.30% and a yield of 63.45%.

[0150] MS(ESI,pos.ion)m / z:490.70[M+H] + ;

[0151] 1 H NMR (400MHz, CDCl3) δ8.45(s,2H),8.37(d,J=8.6Hz,2H),7.69(d,J=8.0Hz,2H),7.45(s,4H),7.41 (s,6H),7.27–7.21(m,2H),7.15(s,2H),7.09(t,J=7.3Hz,2H),6.84(s,2H),4.99(s,2H),4.19(s,4 H),3.93(d,J=8.7Hz,12H),3.63(d,J=17.3Hz,2H),3.49(s,4H),2.83(d,J=17.3Hz,4H),2.56(s,4H ),2.10–1.83(m,8H),1.65(d,J=11.1Hz,10H),1.49–1.38(m,4H),1.27(s,2H),1.25–1.06(m,10H).

[0152] Example 13: In vitro liver microsomal experiment

[0153] 1. Experimental Method:

[0154] 1) Sample preparation

[0155] Prepare a solution by adding 495 μL of 50% ACN / H2O diluent to 5 μL of the test compound or control compound (10 mM) (Conc.: 100 μM, 10% DMSO, 45% ACN);

[0156] 02: Take 60 μL (100 μM) of the prepared _01 solution and dilute it with 140 μL of buffer (Conc.: 30 μM, 3% DMSO, 13.5% ACN);

[0157] 2) Prepare 96-well plates and name them T0, T20, T60, NCF60 (add more if needed);

[0158] 3) Take 18.8 μL (20 mg / mL) of liver microsomal solution and dilute it with 456.2 μL of buffer. Then, incubate the above-prepared sample solution and liver microsomal solution at 37 °C for 10 min.

[0159] 4) Take 25 μL of the above sample solution into the liver microsome solution and shake well; quickly remove 30 μL, add the remaining reaction solution to the reaction termination solution (150 μL / well) and 15 μL NAD, and record the pH as T0.

[0160] 5) Add the 30 μL of the above-extracted mixture to NCF60, T60 and T20 respectively. Add 15 μL of buffer to NCF60 and 15 μL of NADpH (T60, T20) at the corresponding time points respectively; the final reaction system contains 0.5 mg / mL liver microsomes and 2 mM NADpH (Conc.: 1 μM, 0.1% DMSO, 0.45% ACN).

[0161] 6) The reaction was terminated by adding the reaction stop solution (150 μL / well) at 20 and 60 min respectively.

[0162] 7) Centrifuge at 4000 rpm for 5 min.

[0163] 8) Take another 96-well plate and add 150 μL of MeOH / H2O (1:1). Then take 30 μL of the above reaction solution and add it to the diluent to measure LC / MS / MS.

[0164] 2. Experimental results: See Table 1

[0165] Table 1: Stability of the compounds of this invention in human liver microparticles (in vitro)

[0166]

[0167] Experimental results show that all compounds described in this invention, except for compound (11), can metabolize donepezil precursor drug at extremely fast rates.

[0168] Example 14: Determination of compound solubility

[0169] 1. Experimental Method:

[0170] Unless otherwise specified, weigh the finely ground test sample or measure the liquid sample, and in a certain amount of solvent at 25±2℃, shake vigorously for 0.5 minutes every 5 minutes; observe the dissolution within 30 minutes. If no solute particles or droplets are visible to the naked eye, it is considered to be completely dissolved.

[0171] Very soluble means that 1g (mL) of solute can dissolve in less than 1mL of solvent;

[0172] Easily soluble means that 1g (mL) of solute can dissolve in 1 to less than 10mL of solvent;

[0173] Dissolution refers to the ability of 1g (mL) of solute to dissolve in 10 to less than 30mL of solvent;

[0174] Slightly soluble means that 1g (mL) of solute can dissolve in 30 to less than 100mL of solvent;

[0175] Slightly soluble means that 1g (mL) of solute can dissolve in 100 to less than 1000mL of solvent;

[0176] Very slightly soluble means that 1g (mL) of solute can dissolve in 1000 to less than 10000mL of solvent;

[0177] It is almost insoluble or insoluble; 1 g (mL) cannot be dissolved in 10,000 mL of solvent.

[0178] 2. The results are shown in Table 2.

[0179] Table 2: Solubility of the compounds of the present invention in water.

[0180]

[0181]

[0182] The results show that the compound described in this invention has low solubility and is suitable as a long-acting formulation.

[0183] Example 15: Preparation of Suspension

[0184] prescription

[0185] raw materials Prescription 1 (mg / ml) Prescription 2 (mg / ml) Prescription 3 (mg / ml) Prescription 4 (mg / ml) Compound (3) 170 / / / Compound (7) / 179 / / Compound (5) / / 164 / Donepezil dihydroxynaphthyl salt / / / 160 Polosham 407 10 10 10 10 CMC-Na 5 5 5 5 Sodium dihydrogen phosphate monohydrate 1.0 1.0 1.0 1.0 Anhydrous disodium hydrogen phosphate 1.8 1.8 1.8 1.8 Sodium chloride 5.0 5.0 5.0 5.0 Water for Injection qs1ml qs1ml qs1ml qs1ml

[0186] Note: / indicates none.

[0187] Preparation method:

[0188] Step 1. Add the prescribed amount of wetting agent poloxamer 407, stabilizer CMC-Na, sodium chloride and other excipients to an appropriate amount of water for injection and dissolve completely; then add an appropriate amount of sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate to adjust the pH and filter for sterilization.

[0189] Step 2. Add the compound to the mixture from Step 1 and stir to disperse it evenly.

[0190] Step 3. Process the suspension from Step 2 to a suitable particle size using appropriate methods such as media grinding or high-pressure homogenization.

[0191] Example 16: Pharmacokinetic properties of the compounds of the present invention after administration

[0192] 1. Experimental Methods

[0193] The male SD rats (SPF grade) used in this example, aged 8 weeks and weighing 240–275g, were purchased from Hunan Silek Laboratory Animal Co., Ltd. Throughout the experiment, the rats had free access to food and water.

[0194] SD rats of similar weight were selected and randomly divided into groups of 3 rats each: compound (3), compound (5), compound (7), and donepezil dihydroxynaphthyl salt group. All rats were administered the compound via intramuscular injection (IM) at a dose of 50 mg / rat (calculated as donepezil). The sample was dissolved in a solvent at a concentration of 100 mg / mL (calculated as donepezil).

[0195] 0.5h, 1h, 2h, 4h, 6h, 8h, 2 days, 3 days, 4 days, 5 days, 7 days, 9 days, 12 days, 14 days, 17 days, 21 days after drug administration

[0196] 0.5 mL of venous blood was collected from the jugular vein into EP tubes labeled with EDTA (15%) anticoagulation. After whole blood collection, the tubes were placed on ice and then centrifuged at 4°C, 12000 rpm for 5 min to collect plasma. The plasma was transferred to a cryovial and stored at -70°C for LC-MS / MS analysis. The drug concentration in the plasma of EDTA (15%) anticoagulated SD rats was determined using LC / MS / MS (AB 5500). Pharmacokinetic parameters after rat drug administration were calculated using a non-compartmental model in Phoenix WinNonlin 5.2 software. The relevant pharmacokinetic parameters at each time point are detailed in Table 3. The mean plasma concentration-time curves for each group are shown below. Figure 1 .

[0197] 2. Experimental Results

[0198] Table 3. Pharmacokinetic parameters of donepezil:

[0199]

[0200] Both Cmax and Tmax are expressed as measured values.

[0201] T 1 / 2 Use formula T 1 / 2 =0.693 / ke, where ke is the terminal elimination rate constant obtained from the linear portion at the end of the logarithmic concentration-time curve, and can be obtained from the slope of the linear portion at the end of the logarithmic concentration-time curve.

[0202] Area under the curve (AUC) during drug administration INF Value: Calculated using the trapezoidal rule; AUC INF =AUC last +Ct / ke, where Ct is the blood drug concentration at the last measurable time point.

[0203] As can be seen from the above experimental results, the compound of the present invention has a long half-life, the drug maintains a stable concentration in the body, the drug can act for a longer period of time, and the occurrence of adverse reactions can be reduced.

[0204] As can be seen from the test results of Examples 13, 14 and 16 above, the compounds of the present invention have low solubility, rapid metabolism of the original drug in human liver microparticles, and the drug concentration of the injection solution remains stable in vivo. The salts of the compounds of the present invention have the potential to be long-acting drugs.

[0205] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0206] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A salt of a compound having the structure shown below: 。 2. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: the salt of claim 1; The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

3. Use of the salt of claim 1, or the pharmaceutical composition of claim 2, in the preparation of a medicament for inhibiting acetylcholinesterase expression or for the prevention and / or treatment of Alzheimer's disease.

4. The use according to claim 3, characterized in that, The dosage form of the drug is selected from injections, tablets, capsules, or granules.

Images