Salt of donepezil derivative and application of salt in medicine

Abstract

The invention relates to a salt of a donepezil derivative and application of the donepezil derivative in medicine, in particular to a salt of a compound shown in a formula (I), the salt of the compound can play a long-acting role in inhibiting expression of acetylcholinesterase so as to prevent and / or treat Alzheimer's disease in a long-acting mode, and R1 has the meaning described in the invention. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology. Specifically, the present invention relates to a salt of donepezil and a donepezil derivative, and further relates to the use of a salt of a donepezil derivative or a composition of a salt of a donepezil derivative in the preparation of a drug, particularly in the preparation of a drug for the treatment of Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system with a latent onset and a chronic progressive course. It is mainly manifested as progressive memory impairment, cognitive dysfunction, personality changes, language disorders and other neuropsychiatric symptoms, seriously affecting social, occupational and life functions. The cholinergic hypothesis holds that the pathophysiology of cognitive impairment associated with AD is attributed to the destruction or loss of cholinergic neurons, resulting in a decrease in acetylcholine levels, thereby leading to a series of pathological features such as cognitive dysfunction. Acetylcholinesterase (AChE) is a highly efficient hydrolase that catalyzes the hydrolysis of acetylcholine to produce choline and acetate ions. By reversibly inhibiting the activity of acetylcholinesterase, reducing the hydrolysis of acetylcholine and thus increasing the content of acetylcholine at the receptor site can improve the symptoms.

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

[0004] In order to facilitate Alzheimer's disease patients to reduce the frequency of taking medicine, increase the convenience of taking medicine and improve patient compliance, while maintaining the drug treatment concentration for a long time, developing a long-acting sustained-release injection is a better way to solve the related problems. In patent application CN109803654A, donepezil pamoate was developed into a long-acting injection, but the related development was stopped after it was advanced to clinical phase I. The inventor of the present invention tried related experiments and found that donepezil pamoate would cause an initial burst release in the early stage of injection in animals, resulting in too high blood drug concentration and causing adverse reactions.

[0005] Therefore, it is necessary to develop a more long-acting and safer parenteral drug. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art to some extent. The present invention provides a salt of a donepezil derivative, which has low solubility and is suitable as a long-acting preparation.

[0007] On the one hand, the present invention relates to a salt of a compound represented by formula (I).

[0008]

[0009] Among them, R 1 is C 1-21 alkyl, C 3-6 cycloalkyl or C 6-10 aromatic ring, where the C 1-21 alkyl, C 3-6 cycloalkyl and C 6-10 aromatic ring are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 alkyl and C 1-4 alkoxy;

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

[0011] In some embodiments of the present invention, R 1 is C 1-5 alkyl, C 6-15 alkyl, C 16-21 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, where the C 1 -C 5 alkyl, C 6 -C 15 alkyl, C 16 -C 21 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 alkyl and C 1-4 alkoxy.

[0012] In some embodiments of the present invention, R 1 is methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, where the methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl are each independently 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.

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

[0014]

[0015] Among them, in the pamoates formed by all donepezil derivatives, the 2 under the donepezil derivative indicates that 2 donepezil derivative molecules and 1 pamoic acid molecule form a salt.

[0016] On the other hand, the present invention relates to a pharmaceutical composition, which comprises the salt described in the present invention;

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

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

[0019] In some embodiments of the present invention, the dosage form of the medicament is selected from injection, tablet, capsule or granule.

[0020] Detailed description of the present invention

[0021] The present invention is intended to cover all alternative, modification and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

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

[0023] Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. All patents and published publications referred to in the present invention are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described in the present invention can be used in the practice or testing of the present invention, the methods, devices and materials described in the present invention are preferred.

[0024] Definitions and general terms

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

[0026] In the present 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] In addition, it should be noted that, unless otherwise explicitly stated, the description methods "each... and... independently is", "... and... each independently is" and "... and... are independently respectively" adopted throughout this article can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0028] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group types or ranges. It is specifically pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl independently disclosed.

[0029] The term "alkyl" used in the present invention includes a saturated straight-chain or branched-chain monovalent hydrocarbon group having 1 to 20 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, in other embodiments, the alkyl group contains 1 to 10 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of the alkyl group include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 )2 )), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ))), tert-butyl (t-Bu, -C(CH 3 ))) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ))), 2-pentyl (-CH(CH 3 ))CH 2 CH 2 CH 3 ))), 3-pentyl (-CH(CH 2 CH 3 ))) 2 ), 2-methyl-2-butyl (-C(CH 3 ))) 2 CH 2 CH 3 ))), 3-methyl-2-butyl (-CH(CH 3 ))CH(CH 3 ))) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ))) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ))CH 2 CH 3 ))), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ))), 2-hexyl (-CH(CH 3 ))CH 2 CH 2 CH 2 CH 3 ))), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))), 2-methyl-2-pentyl (-C(CH 3 ))) 2 CH 2 CH 2 CH 3 ))), 3-methyl-2-pentyl (-CH(CH3 )CH(CH 3 )CH 2 CH 3 )、4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 )、3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 )、2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 )、n-heptyl, n-octyl, and so on.

[0030] The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic saturated system, mono- or polyvalent, containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl contains 3 to 8 carbon atoms; in another embodiment, the cycloalkyl contains 3 to 7 carbon atoms; in still other embodiments, the cycloalkyl contains 3 to 6 carbon atoms. Examples of cycloalkyl further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0031] The term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, each ring system contains a ring composed of 3 to 7 atoms, and there is one or more connection points to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl, and anthracenyl. The aryl groups can be independently optionally substituted by one or more substituents described in the present invention.

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

[0033] As used herein, the term "treat" or "treatment" of any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of its clinical symptoms). In other embodiments, "treat" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceptible to the patient. In other embodiments, "treat" refers to modulating the disease or disorder physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter) or both. In other embodiments, "treat" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder.

[0034] The salts of the compounds of formula (I) of the present invention or their pharmaceutical compositions

[0035] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, which, for example as used in the present invention, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder, glidant or lubricant, etc., suitable for the particular target dosage form. As described in the following references: 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 combined teachings of these references indicate that different excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Their use is also contemplated by the present invention to the extent that any conventional excipient is not incompatible with the compounds of the present invention, e.g., any adverse biological effects that may result or interactions that may occur in a harmful manner with any other component of the pharmaceutically acceptable composition.

[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; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polypropylene-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl 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; diol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating materials; sweeteners; flavoring agents; fragrances; preservatives and antioxidants.

[0037] The cocrystals or pharmaceutical compositions of the compounds described in the present invention can be administered in any of the following ways: oral administration, aerosol inhalation, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intracardiac, intrasternal, or intracranial injection or infusion, or administration by means of an implanted reservoir. Preferred ways are oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.

[0038] The cocrystals of the compounds described in the present invention or the compositions containing pharmaceutically acceptable ones can be administered in unit dosage form. The dosage forms can be liquid dosage forms, solid dosage forms. Liquid dosage forms can be true solution types, colloidal types, particulate dosage forms, suspension dosage forms. Other dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc.

[0039] Oral tablets and capsules can contain excipients such as binders, such as syrup, gum arabic, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets can be coated by methods well known in the pharmaceutical art.

[0040] The oral liquid can be made into suspensions, solutions, emulsions, syrups or elixirs of water and oil, or can be made into dry products, with water or other suitable media added before use. Such liquid preparations can contain conventional additives, such as suspending agents, sorbitol, methylcellulose, glucose syrup, gels, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oils, emulsifying agents, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous carriers (which may contain edible oils), such as almond oil, oils such as glycerol, ethylene glycol, or ethanol; preservatives, such as methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring agents or coloring agents can be added if needed.

[0041] Suppositories can contain conventional suppository bases, such as cocoa butter or other glycerides.

[0042] For parenteral administration, the liquid dosage form is usually made from the compound and a sterilized carrier. The preferred carrier is water. Depending on the selected carrier and the drug concentration, the compound can either be dissolved in the carrier or made into a suspension solution. When making an injectable solution, the compound is first dissolved in water, filtered and sterilized, and then filled into sealed bottles or ampoules.

[0043] When topically applied to the skin, the compounds or co-crystals of the present invention can be made into suitable ointments, lotions, or creams, in which the active ingredient is suspended or dissolved in one or more carriers. The carriers that can be used in ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; the carriers that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0044] Generally speaking, it has been proven beneficial that, whether in human medicine or veterinary medicine, the total dosage of the active compound of the present invention per 24 hours is about 0.5 - 500 mg, preferably 1 - 100 mg / kg body weight. If appropriate, it is administered in multiple single doses to achieve the desired effect. The amount of the active compound in a single dose is preferably about 1 - 80 mg, more preferably 1 - 50 mg / kg body weight, but it can also not follow the above dosage, that is, depending on the type and weight of the treatment object, the nature and severity of the disease, the type of the preparation and the mode of drug administration, as well as the administration cycle or time interval.

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

[0046] The characteristics of the pharmaceutical composition of the present invention include the salts of the compounds of formula (I), such as the salts of the compounds shown in formula (I), and pharmaceutically acceptable excipients. The salts or their pharmaceutical compositions of the present invention can effectively inhibit acetylcholinesterase and are applicable to the treatment of Alzheimer's disease, especially applicable to diseases or symptoms caused by acetylcholinesterase.

[0047] The "effective amount", "effective therapeutic amount" or "effective dose" of the salts of the compounds of the present invention and / or pharmaceutically acceptable pharmaceutical compositions refers to an effective amount for treating or alleviating the severity of one or more of the disorders mentioned in the present invention. The salts or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective within a relatively wide dosage range. For example, the daily dosage is about in the range of 0.1 mg - 100 mg / kg, administered once or in several divided doses. According to the method of the present invention, the cocrystals and / or pharmaceutical compositions can be effectively used for treating or alleviating the severity of the disease by any dosage and any route of administration. The exact amount required will vary according to the patient's condition, depending on age, the general condition of the patient, the severity of the infection, special factors, the mode of administration, etc. The salts or pharmaceutical compositions of the compounds of the present invention can be administered in combination with one or more other therapeutic agents, as discussed in the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Shows the mean plasma concentration-time curves of compounds (3), (5), (7) and donepezil pamoate. DETAILED DESCRIPTION OF THE INVENTION

[0049] The embodiments of the present invention will be described in detail below. The examples of the embodiments are shown in the drawings. The embodiments described below by referring to the drawings are exemplary and are 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 of ordinary skill in the art can more easily understand the features and advantages of the present invention. It should be understood that for the sake of clarity, certain features of the present invention described above and in the context of the following individual embodiments may also be combined to form a single embodiment. On the contrary, for the sake of brevity, the different features described in the context of a single embodiment may also be combined to form their sub-combinations. The disclosure of the present invention is further illustrated by the following examples, but these examples should not be construed as limiting the scope of the present invention or being limited to the specific steps described therein.

[0052] In the embodiments described below, unless otherwise indicated, all temperatures are in degrees Celsius (°C). Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory.

[0053] The eutectics prepared in the present invention were identified by the following methods:

[0054] The X-ray powder diffraction (PXRD) analysis method used in the present invention was as follows: PANalytical diffractometer, the radiation source used was (Cu, kα, 1.540598; 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage was set at 45 KV and the current was set at 40 mA. 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 the range of 3° to 40° with a step size of 0.0168°. 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 the present invention was as follows: Differential scanning calorimetry was performed using a TA Q2000 module with a thermal analysis controller. Data was collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1 - 5 mg of the sample was accurately weighed into a special aluminum crucible with a lid, and the sample was analyzed from room temperature to approximately 300 °C using a linear heating device at 10 °C / min. During use, the DSC cell was purged with dry nitrogen at 50 mL / min. The plot was made with the endothermic peak downward, and the data was analyzed and presented using TA Universal Analysis.

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

[0057] The solubility of the present invention was determined using a VWD detector of an Aglient 1200 high performance liquid chromatograph. The chromatographic column model was 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] The chromatographic column used was a silica gel column, and the silica gel (200 - 300 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectral data was determined using a Bruker Avance400 nuclear magnetic resonance spectrometer or a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, with CDC1 3 ,d 6 -DMSO, CD 3 OD or d 6 -acetone as the solvent (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks appeared, the following abbreviations were used: s (singlet), s, s (singlet, singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets), td (triplet of doublets), brs (broadened singlet). The coupling constant was expressed in hertz (Hz).

[0059] Low-resolution mass spectrometry (MS) data was determined by spectrometers of Agilent 6320 series LC-MS 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 applied for analysis, and an ESI source was applied to the LC-MS spectrometer. Low-resolution mass spectrometry (MS) data was determined by spectrometers of Agilent 6120 series LC-MS 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 applied for analysis, and an ESI source was applied to the LC-MS spectrometer. LCMS was performed with gradient elution using high performance liquid chromatography (manufacturer: Agilent, model: 1200), scanned in positive ion mode, and the mass scan range was

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

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

[0062]

[0063]

[0064] The compound purity was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was performed at 210 nm and 254 nm. The preparative separation of compound chromatography was achieved by Agilent 1260 series high performance liquid chromatography (HPLC).

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

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

[0067] The following abbreviations are used throughout the present invention:

[0068] THF tetrahydrofuran EA ethyl acetate

[0069] Lithium bis(trimethylsilyl)amide (LiHMDS), Dichloromethane (DCM)

[0070] Dimethyl sulfoxide (DMSO)

[0071] Preparation of Compound (1) in Example 1

[0072]

[0073] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into a reaction flask respectively. Under nitrogen protection, at -30 °C, 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 continuously reacted at -30 °C for 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the organic phase was obtained by liquid separation.

[0074] The solvent of the obtained organic phase was removed under reduced pressure by rotary evaporation. The obtained residue was added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and the mixture was reacted at 50 °C for 4 h. After suction 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 obtained reaction mixture was stirred at room temperature for 3 h, and then separated by liquid separation. The organic phase was concentrated under reduced pressure, and the residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil acetate with a yield of 75%.

[0075] The obtained donepezil acetate (1.00 eq), ditaninic acid (0.50 eq) and DMSO (3.00 vol) were added to a reaction flask, and then 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. After suction filtration and drying of the filter cake, absolute ethanol (40.00 vol) was added and the mixture was slurried 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 (400 MHz, CDCl 3)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] Preparation of Compound (2) in Example 2

[0079]

[0080] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into a reaction flask respectively. Under nitrogen protection, at -30 °C, 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 continued to react at -30 °C for 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the organic phase was obtained by liquid separation.

[0081] The solvent of the above-obtained organic phase was removed under reduced pressure. The obtained residue was added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and the mixture was reacted at 50 °C for 4 h. After suction 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 obtained reaction mixture was stirred at room temperature for 3 h, and the organic phase was separated by liquid separation and concentrated under reduced pressure. The residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil propionate, with a yield of 68%.

[0082] The obtained donepezil acetate (1.00 eq), ditanate (0.50 eq) and DMSO (3.00 vol) were added to a reaction flask, and then 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. After suction filtration and drying of the filter cake, absolute ethanol (40.00 vol) was added and the mixture was slurried 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 (400 MHz, CDCl 3 ) δ 8.49 (s, 2H), 8.43 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.58–7.46 (m, 4H), 7.43 (d, J = 5.1 Hz, 6H), 7.31 (dd, J = 6.9, 1.5 Hz, 2H), 7.13 (t, J = 7.4 Hz, 2H), 6.94 (s, 2H), 6.57 (s, 2H), 5.04 (s, 2H), 4.23 (s, 4H), 3.86 (d, J = 11.3 Hz, 12H), 3.58 (s, 6H), 3.24 (s, 4H), 2.54 (q, J = 7.5 Hz, 8H), 2.36 (d, J = 6.9 Hz, 4H), 1.86 (d, J = 21.9 Hz, 8H), 1.68 (s, 2H), 1.28 (s, 2H), 1.17 (t, J = 7.5 Hz, 6H).

[0085] Preparation of Compound (3) in Example 3

[0086]

[0087] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into a reaction flask respectively. Under nitrogen protection, at -30 °C, 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 continued to react at -30 °C for 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the organic phase was obtained by liquid separation.

[0088] The solvent of the obtained organic phase above was removed under reduced pressure. The obtained residue was added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol), and the mixture was reacted at 50 °C for 4 h. After suction 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 obtained reaction mixture was stirred at room temperature for 3 h, and then liquid separation was carried out. The organic phase was concentrated under reduced pressure, and the residue was slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain the donepezil butyryl ester with a yield of 72%.

[0089] The obtained donepezil butyrate (1.00 eq), ditropic acid (0.50 eq) and DMSO (3.00 vol) were added to a reaction flask, and then reacted at room temperature for 2 h. Purified water (100.00 vol) was added, and stirring was continued for 0.5 h. After filtration, the filter cake was dried, anhydrous ethanol (40.00 vol) was added, and the mixture was slurried 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] 1 H 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,2H),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] Preparation of the compound (4) in Example 4

[0093]

[0094] Donepezil (1.00 eq) and THF (5.00 vol) were weighed into a reaction flask under nitrogen protection. At -30 °C, 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 continued to react at -30 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution, and the organic phase was obtained by liquid separation.

[0095] The solvent was removed from the organic phase obtained above under reduced pressure, and 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol) were added to the residue, and the mixture was reacted at 50° C. for 4 h. The mixture was filtered and the filter cake was dried. Then, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The reaction mixture was stirred and reacted at room temperature for 3 h. The liquids were 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 butyrate in a yield of 72%.

[0096] Donepezil butyrate (1.00 eq), oxalic acid (1.00 eq) and acetone (20.00 vol) were added to a reaction flask, and the reaction was placed at 50°C for 5 h, filtered, and the filter cake was rinsed 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] 1 H 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 bottle respectively, and LiHMDS (2.00 eq) was added at -30°C under nitrogen protection. The mixture was allowed to react for 3 h at -30°C, and then butyric anhydride (2.50 eq) was added. The reaction mixture was continued to react for 2 h at -30°C. A saturated ammonium chloride solution was added to quench the reaction, and the liquids were separated to obtain an organic phase.

[0102] The solvent was removed from the organic phase obtained above under reduced pressure, and 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol) were added to the residue, and the mixture was reacted at 50° C. for 4 h. The mixture was filtered and the filter cake was dried. Then, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The reaction mixture was stirred and reacted at room temperature for 3 h. The liquids were 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 butyrate.

[0103] Donepezil butyrate (1.00 eq), p-toluenesulfonic acid (1.00 eq) and ethyl acetate (10.00 vol) were added to the reaction flask, and the reaction was placed at 50°C for 5 h, filtered, and the filter cake was rinsed 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] 1 H 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 bottle respectively, and LiHMDS (2.00 eq) was added at -30°C under nitrogen protection. The mixture was allowed to react for 3 h at -30°C, and then butyric anhydride (2.50 eq) was added. The reaction mixture was continued to react for 2 h at -30°C. A saturated ammonium chloride solution was added to quench the reaction, and the liquids were separated to obtain an organic phase.

[0109] The solvent was removed from the organic phase obtained above under reduced pressure, and 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol) were added to the residue, and the mixture was reacted at 50° C. for 4 h. The mixture was filtered and the filter cake was dried. Then, sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol) were added. The reaction mixture was stirred and reacted at room temperature for 3 h. The liquids were 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 butyrate.

[0110] The above-obtained donepezil butyrate (1.00 eq), 3-hydroxy-2-naphthoic acid (1.00 eq) and acetone (10.00 vol) were added to a reaction bottle, and then reacted at 50° C. for 5 h. After suction filtration and filter cake drying, 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] 1 H NMR (400 MHz, CDCl 3 )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),3.8 7(s,6H),3.54(s,2H),3.24(s,2H),2.54(t,J=7.3Hz,4H),2.34(d,J=6.7 Hz,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 bottle respectively, and LiHMDS (2.00 eq) was added at -30°C under nitrogen protection. The mixture was allowed to react for 3 h at -30°C, and then benzoic anhydride (2.50 eq) was added. The reaction mixture was continued to react for 2 h at -30°C. A saturated ammonium chloride solution was added to quench the reaction, and the liquids were separated to obtain an organic phase.

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

[0117] Donepezil benzoyl ester (1.00 eq), ditropic acid (0.50 eq) and DMSO (3.00 vol) obtained above were added to a reaction flask, and then 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. After suction filtration, the filter cake was dried, then added with absolute ethanol (40.00 vol) and slurried at 50 °C for 1 h. After suction filtration and drying, the target product had 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),7.64–7.58(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=7.4Hz,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] Preparation of the compound (8) in Example 8

[0121]

[0122] Weigh donepezil (1.00 eq) and THF (5.00 vol) into a reaction flask respectively. Under nitrogen protection, at -30 °C, add LiHMDS (2.00 eq) and react at -30 °C for 3 h. Then add benzoic anhydride (2.50 eq) and continue to react the reaction mixture at -30 °C for 2 h. Quench the reaction by adding saturated ammonium chloride solution, separate the layers, and obtain the organic phase.

[0123] Remove the solvent from the above-obtained organic phase under reduced pressure. Add 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol) to the obtained residue, and react at 50 °C for 4 h. Filter by suction. After drying the filter cake, add sodium hydroxide (5.00 eq), DCM (10.00 vol), and purified water (10.00 vol). Stir and react the obtained reaction mixture at room temperature for 3 h, separate the layers, concentrate the organic phase under reduced pressure, and slurry the residue with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0124] Add the above-obtained donepezil benzoyl ester (1.00 eq), oxalic acid (1.00 eq), and acetone (20.00 vol) to a reaction flask, then react at 50 °C for 5 h. After cooling to room temperature, filter by suction, wash the filter cake with acetone, and dry the filter cake 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,CDCl 3 )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] Preparation of the compound (9) in Example 9

[0128]

[0129] Weigh donepezil (1.00 eq) and THF (5.00 vol) into a reaction flask respectively. Under nitrogen protection, at -30 °C, add LiHMDS (2.00 eq) again, place it at -30 °C and react for 3 h, then add benzoic anhydride (2.50 eq), and continue to react the reaction mixture at -30 °C for 2 h. Add saturated ammonium chloride solution to quench the reaction, separate the liquid, and obtain the organic phase.

[0130] Remove the solvent from the above-obtained organic phase under reduced pressure. Add 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol) to the obtained residue, place it at 50 °C and react for 4 h. Filter by suction. After drying the filter cake, add sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol). Stir and react the obtained reaction mixture at room temperature for 3 h, separate the liquid, concentrate the organic phase under reduced pressure, and slurry the residue with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0131] Add the above-obtained donepezil benzoyl ester (1.00 eq), p-toluenesulfonic acid (1.00 eq) and acetone (20.00 vol) to a reaction flask, then place it at 50 °C and react for 5 h. After cooling to room temperature, filter by suction, wash the filter cake with acetone, and dry the filter cake 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] 1 H 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,1H),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] Preparation of the compound (10) in Example 10

[0135]

[0136] Weigh donepezil (1.00 eq) and THF (5.00 vol) into a reaction flask respectively. Under nitrogen protection, at -30 °C, add LiHMDS (2.00 eq) again. Place it at -30 °C and react for 3 h. Then add benzoic anhydride (2.50 eq). The reaction mixture continues to react at -30 °C for 2 h. Add saturated ammonium chloride solution to quench the reaction. Separate the layers to obtain the organic phase.

[0137] The organic phase obtained above is rotary-evaporated under reduced pressure to remove the solvent. The resulting residue is added with 3-hydroxy-2-naphthoic acid (1.10 eq) and EA (10.00 vol). Place it at 50 °C and react for 4 h. Filter by suction. After the filter cake is dried, add sodium hydroxide (5.00 eq), DCM (10.00 vol) and purified water (10.00 vol). The resulting reaction mixture is stirred at room temperature for 3 h. Separate the layers. The organic phase is concentrated under reduced pressure. The residue is slurried with n-hexane (10.00 vol) at 60 °C for 3 h to obtain donepezil benzoyl ester.

[0138] Add the donepezil benzoyl ester (1.00 eq), phosphoric acid (1.00 eq) and ethyl acetate (20.00 vol) obtained above into a reaction flask. Then place it at 50 °C and react for 5 h. Cool down to room temperature. Filter by suction. The filter cake is rinsed 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] 1 H NMR(400MHz,CDCl 3 )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,2H),1.71(s,2H),1.57(d,J=8.7Hz,1H),1.46(d,J=9.5Hz,1H),1.32(s,4H).

[0141] Preparation of the compound (11) in Example 11

[0142]

[0143] Weigh donepezil (1.00 eq) and THF (40.00 vol) into a reaction flask respectively. Under nitrogen protection, at -25 °C, add LiHMDS (1.500 eq) again, place it at -30 °C and react for 2 h. Then add p-toluoyl chloride (1.50 eq), move the reaction flask to room temperature and react for 2 h. Add methanol to quench the reaction, rotary evaporate to dryness. Dissolve the residue in DCM, wash with water, concentrate the organic phase under reduced pressure. The obtained residue is purified by silica gel column (n-hexane / EA (V / V) = 6 / 4) to obtain white solid donepezil p-methylbenzoate.

[0144] Add the obtained donepezil p-methylbenzoate (1.00 eq), ditropic acid (0.50 eq) and DMSO (3.00 vol) into a reaction flask, then place it at room temperature and react for 2 h. Add purified water (100.00 vol), and continue to stir for 0.5 h. Filter by suction. After the filter cake is dried, add absolute ethanol (40.00 vol) and slurry at 50 °C for 1 h. Filter by suction and dry 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] Preparation of compound (12) in Example 12

[0147]

[0148] Weigh donepezil (1.00 eq) and THF (40.00 vol) into a reaction flask respectively. Under nitrogen protection, at -25 °C, add LiHMDS (1.500 eq) again, place it at -30 °C and react for 2 h. Then add cyclohexanecarbonyl chloride (1.50 eq), move the reaction flask to room temperature and react for 2 h. Add methanol to quench the reaction, rotary evaporate to dryness. Dissolve the residue in DCM, wash with water, concentrate the organic phase under reduced pressure. The obtained residue is purified by silica gel column (n-hexane / EA (V / V) = 6 / 4) to obtain light orange solid donepezil cyclohexanecarboxylate.

[0149] Add the obtained donepezil cyclohexanecarboxylate (1.00 eq), ditropic acid (0.50 eq) and DMSO (3.00 vol) into a reaction flask, then place it at room temperature and react for 2 h. Add purified water (100.00 vol), and continue to stir for 0.5 h. Filter by suction. After the filter cake is dried, add absolute ethanol (40.00 vol) and slurry at 50 °C for 1 h. Filter by suction and dry 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 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 8.37 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.45 (s, 4H), 7.41 (s, 6H), 7.27–7.21 (m, 2H), 7.15 (s, 2H), 7.09 (t, J = 7.3 Hz, 2H), 6.84 (s, 2H), 4.99 (s, 2H), 4.19 (s, 4H), 3.93 (d, J = 8.7 Hz, 12H), 3.63 (d, J = 17.3 Hz, 2H), 3.49 (s, 4H), 2.83 (d, J = 17.3 Hz, 4H), 2.56 (s, 4H), 2.10–1.83 (m, 8H), 1.65 (d, J = 11.1 Hz, 10H), 1.49–1.38 (m, 4H), 1.27 (s, 2H), 1.25–1.06 (m, 10H).

[0152] Example 13: In Vitro Liver Microsome Experiment

[0153] 1. Experimental Method:

[0154] 1) Sample Preparation

[0155] 01: Add 5 μL of the test compound or control compound (10 mM) to 495 μL of 50% ACN / H 2 O dilution solution (Conc.: 100 μM, 10% DMSO, 45% ACN);

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

[0157] 2) Prepare a 96-well plate and name it T0, T20, T60, NCF60 (additional wells can be added if necessary);

[0158] 3) Dilute 18.8 μL (20 mg / mL) of liver microsome solution with 456.2 μL of buffer, and then incubate the above-prepared sample solution and liver microsome solution at 37 °C for 10 min;

[0159] 4) Take 25 μL of the above sample solution and add it to the liver microsome solution and shake well; quickly take out 30 μL, and add the reaction termination solution (150 μL / well) and 15 μL of NADpH to the remaining reaction solution and label it as T0.

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

[0161] 6) Add the reaction termination solution (150 μL / well) to terminate the reaction at 20 and 60 min of reaction respectively.

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

[0163] 8) Take another 96 - well plate and add 150 μL of MeOH / H 2 O (1:1), and 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 the present invention in human liver microsomes (in vitro)

[0166]

[0167] The experimental results show that all the compounds of the present invention, except for compound (11), can metabolize the prototype drug of donepezil, and the metabolic rate is extremely fast.

[0168] Example 14: Determination of compound solubility

[0169] 1. Experimental method:

[0170] Unless otherwise specified, weigh the test sample ground into fine powder or measure the liquid sample, place it in a certain amount of solvent at 25 ± 2 °C, shake vigorously for 0.5 min every 5 min; observe the dissolution situation within 30 min. If there are no visually visible solute particles or droplets, it is regarded as completely dissolved.

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

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

[0173] Soluble means that 1 g (mL) of solute can dissolve in 10 - less than 30 mL of solvent;

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

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

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

[0177] Practically insoluble or insoluble means that 1 g (mL) of solute cannot dissolve in 10000 mL of solvent.

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

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

[0180]

[0181]

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

[0183] Example 15: Preparation of suspension

[0184] Prescription

[0185] Raw and auxiliary 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 ditanate / / / 160 Poloxamer 407 10 10 10 10 CMC-Na 5 5 5 5 Sodium dihydrogen phosphate monohydrate 1.0 1.0 1.0 1.0 Disodium hydrogen phosphate anhydrous 1.8 1.8 1.8 1.8 Sodium chloride 5.0 5.0 5.0 5.0 Water for injection q.s. 1 ml q.s. 1 ml q.s. 1 ml q.s. 1 ml

[0186] Note: / indicates none

[0187] Preparation method:

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

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

[0190] Step 3. Use a suitable method such as media grinding or high-pressure homogenization to process the suspension in Step 2 to an appropriate particle size.

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

[0192] 1. Experimental method

[0193] In this example, male SD rats (SPF grade), 8 weeks old, weighing 240 - 275 g, were purchased from Hunan Slack Experimental Animal Co., Ltd. During the entire experimental process, the rats had free access to food and water.

[0194] SD rats with similar body weights were selected and randomly divided into groups of 3 rats each, including a compound (3) group, a compound (5) group, a compound (7) group, and a donepezil embonate group. Each group was administered the drug by intramuscular injection (i.m.), and the dosage was set at 50 mg / rat (calculated as donepezil), and the samples were dissolved in a solvent at a concentration of 100 mg / mL (calculated as donepezil).

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

[0196] 0.5 mL of venous blood was collected from the jugular vein into an EDTA (15%) anticoagulated EP tube. After the whole blood was collected, it was placed on ice and then centrifuged at 4°C and 12,000 rpm for 5 min to collect the plasma, which was transferred to a cryopreservation box and stored at -70°C until LC-MS / MS detection. The LC / MS / MS (AB 5500) method was used to determine the drug concentration in the plasma of EDTA (15%) anticoagulated SD rats. The non-compartmental model of Phoenix WinNonlin 5.2 software was used to calculate the pharmacokinetic parameters of the rats after drug administration. The relevant pharmacokinetic parameters of the concentrations at each time point are shown in Table 3. The average plasma concentration-time curves of each group are shown in Figure 1 .

[0197] 2. Experimental results

[0198] Table 3 Pharmacokinetic parameters of donepezil:

[0199]

[0200] Among them, Cmax and Tmax are both expressed as measured values.

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

[0202] The area under the concentration-time curve AUC INF value: Calculated using the trapezoidal method; AUC INF = AUC last + Ct / ke, where Ct is the plasma drug concentration at the last measurable time point

[0203] From the above experimental results, it can be seen that the compounds of the present invention have a longer half-life, the drug always maintains a stable concentration in the body, the drug can act for a longer time and can reduce the occurrence of adverse reactions.

[0204] From the test results of the above Examples 13, 14, and 16, it can be seen that the compound of the present invention has low solubility, rapidly metabolizes the original drug in human liver microsomes, and the drug concentration in the injection solution always remains stable in the body. The salt of the compound of the present invention has the potential to be a long-acting drug.

[0205] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0206] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill 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 the compound represented by formula (I), wherein, R 1 is C 1-21 alkyl, C 3-6 cycloalkyl or C 6-10 aryl, wherein said C 1-21 alkyl, C 3-6 cycloalkyl and C 6-10 aryl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 alkyl and C 1-4 alkoxy; the salt is pamoate, oxalate, phosphate, p-toluenesulfonate, fumarate or naphthalenesulfonate.

2. The salt according to claim 1, wherein, R 1 is C 1-5 alkyl, C 6-15 alkyl, C 16-21 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the C 1 -C 5 alkyl, C 6 -C 15 alkyl, C 16 -C 21 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl are each independently optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from -OH, -F, -Cl, -Br, -I, =O, C 1-4 alkyl and C 1-4 alkoxy.

3. The salt according to claim 1 or 2, wherein, R 1 is methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, wherein the methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl are each independently 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.

4. The salt according to any one of claims 1-3, which has one of the following structures:

5. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: the salt according to any one of claims 1-4; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

6. Use of the salt according to any one of claims 1-4, or the pharmaceutical composition according to claim 5, in the preparation of a drug for inhibiting the expression of acetylcholinesterase or preventing and / or treating Alzheimer's disease.

7. The use according to claim 6, characterized in that, the dosage form of the drug is selected from injection, tablet, capsule or granule.

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