Prodrug acting on cholinesterase as well as preparation method and application thereof

Abstract

The invention discloses a prodrug acting on cholinesterase as well as a preparation method and application thereof, and belongs to the technical field of medical chemistry. The prodrug is obtained by modifying a phenolic hydroxyl group of a phenol drug of cholinesterase with a group shown in a formula (1): # imgabs0 # (1), wherein R is a metal ion, and the metal ion enables the prodrug to form a pharmaceutically acceptable salt. The preparation method comprises the following steps: by taking the phenol drug acting on cholinesterase as a starting material, carrying out hydroxymethylation reaction, then carrying out chlorination reaction, then carrying out phosphorylation reaction, and finally carrying out salt forming reaction to obtain the prodrug. The pharmaceutical prodrug is good in water solubility, can reduce first-pass metabolism of the phenolic drugs, can be quickly hydrolyzed into drugs under the catalytic action of in-vivo enzyme, and remarkably increases the accumulation amount of the drugs in the brain, so that the drugs can efficiently inhibit cholinesterase activity so as to regulate and control a neurotransmitter metabolic pathway.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a prodrug acting on cholinesterase, a preparation method thereof, and an application thereof. Background Art

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease, clinically manifested as memory disorders such as aphasia, apraxia, and agnosia, visuospatial skill impairment, executive function disorder, and personality and behavior changes. The cholinergic hypothesis points out that the destruction or deficiency of cholinergic neurons will cause a decrease in the level of the neurotransmitter choline, which in turn triggers a series of pathological features such as cognitive dysfunction. Therefore, central nervous system cholinesterase (AChE) has become a target for AD drug research. AChE is an important class of enzymes that terminate signal transmission by hydrolyzing acetylcholine, thereby ensuring the precise regulation of nerve signals, maintaining the normal function of the nervous system, and supporting cognitive ability.

[0003] Cholinesterase inhibitors, as a class of drugs that have been proven and widely used in the treatment of AD, include tacrine, donepezil, rivastigmine, and galantamine, etc. In 1993, tacrine began to be used for clinical treatment. Its inhibitory effect on AChE is significant (IC 50 = 31 nM), and it has high lipid solubility and can easily cross the blood-brain barrier. However, due to oxidative stress, tacrine will cause hepatotoxicity at therapeutic doses, and its treatment requires symptomatic treatment measures such as atropine and antioxidants. Currently, it is no longer recommended for AD treatment. Donepezil (IC 50 = 6.7 nM), rivastigmine (IC 50 = 4.15 μM), and galantamine (IC 50 = 8.5 μM) will cause various gastrointestinal side effects, such as abdominal pain, vomiting, loss of appetite, and may also cause syncope, falls, bradycardia, etc. Therefore, there is an urgent need to develop other pharmaceutical products that can inhibit the action of AChE to treat AD and can be targeted to the central nervous system to avoid the drug being digested and absorbed by the stomach and duodenum. Summary of the Invention

[0004] In view of the above problems, the present invention aims to provide a prodrug acting on cholinesterase, a preparation method thereof, and an application thereof.

[0005] The technical solution of the present invention is as follows: On the one hand, a prodrug acting on cholinesterase is provided, and the prodrug is obtained by modifying the phenolic hydroxyl group of a phenolic drug acting on cholinesterase with the group shown in formula (1): (1) In the formula: R is a metal ion, and the metal ion enables the prodrug to form a pharmaceutically acceptable salt.

[0006] Preferably, the phenolic drug acting on cholinesterase is eugenol, thymol or carvacrol.

[0007] On the other hand, there is also provided a method for preparing the prodrug of the drug acting on cholinesterase according to any one of the above, comprising the following steps: S1: Using the phenolic drug acting on cholinesterase as a starting material, carrying out a hydroxymethylation reaction on it to obtain compound B; S2: Carrying out a chlorination reaction on compound B to obtain compound C; S3: Carrying out phosphorylation on compound C to obtain compound D; S4: Carrying out a salt formation reaction on compound D to obtain the prodrug.

[0008] Preferably, in step S1, the hydroxymethylation reagent used for hydroxymethylation is any one or more of CH 3 I, CH 3 Br, CH 3 Cl, CH 4 .

[0009] Preferably, in step S2, the chlorination reagent used for chlorination is POCl 3 and / or PCl 5 .

[0010] Preferably, in step S4, the salt formation reagent used for salt formation is any one or more of sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, zinc salt, iron salt, lithium salt.

[0011] Preferably, when the salt formation reagent is a sodium salt, the sodium salt is any one or more of sodium hydroxide, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate.

[0012] On the other hand, there is also provided the application of the prodrug of the drug acting on cholinesterase according to any one of the above in the preparation of a cholinesterase inhibitor or a drug for treating central nervous system diseases.

[0013] Preferably, the prodrug is prepared into an injection preparation, and the injection preparation is a solution or a freeze-dried powder.

[0014] Preferably, the solution comprises: prodrug, pH buffer, osmotic pressure regulator, antioxidant and injection water; the concentration of the prodrug is 0.01 - 10 mol / L, the pH adjustment range of the pH buffer is 4.5 - 9.0, the addition amount of the osmotic pressure regulator is 0.3 - 0.9%, the addition amount of the antioxidant is 0 - 0.2%, and the balance is the injection water.

[0015] The beneficial effects of the present invention are as follows: (1) The present invention provides a prodrug, which can solve the problem that drugs cannot be efficiently accumulated in the brain. At the same time, the prodrug is metabolized by alkaline phosphatase into the drug and then targets the central nervous system, and has good cholinesterase inhibitory activity, and is expected to play a role in treating central nervous system diseases, especially treating AD.

[0016] (2) The preparation method of the present invention is simple, and the intermediate products and target products in the preparation process have low toxicity, meeting the requirements of green chemistry. Description of the Drawings

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0018] Figure 1 It is a comparative diagram of in vitro enzymatic hydrolysis kinetics of the prodrug of Example 1 and Comparative Example 1; Figure 2 It is a comparative diagram of the inhibitory effects of the prodrug of Example 1, the prodrug of Comparative Example 1 and carvacrol on acetylcholinesterase. Detailed Embodiments

[0019] The present invention will be further described below in conjunction with the drawings and embodiments. It should be noted that, without conflict, the embodiments in the present application and the technical features in the embodiments can be combined with each other. It should be pointed out that unless otherwise specified, all technical and scientific terms used in the present application have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs. The term "including" or "comprising" and the like used in the present invention means that the elements or objects appearing before the term cover the elements or objects listed after the term and their equivalents, without excluding other elements or objects.

[0020] On the one hand, the present invention provides a prodrug acting on cholinesterase, and the prodrug is obtained by modifying the phenolic hydroxyl group of a phenolic drug acting on cholinesterase with the group shown in formula (1): (1) In the formula: R is a metal ion, and the metal ion makes the prodrug form a pharmaceutically acceptable salt.

[0021] In the present invention, after the prodrug is administered by injection, it can be decomposed under the action of alkaline phosphatase to generate a drug that can rapidly act on the brain. The drug accumulates in the brain and can be rapidly metabolized after exerting its effect, with minimal impact on the body. It can avoid the drawback that the unmodified drug cannot be targeted to the central nervous system and is digested and absorbed by the stomach and duodenum.

[0022] In a specific embodiment, the phenolic drug acting on cholinesterase is eugenol, thymol or carvacrol. That is, the prodrug has the structure shown in formula (2), (3) or (4): (2) (3) (4) On the other hand, the present invention also provides a preparation method of the prodrug of the drug acting on cholinesterase described in any one of the above, including the following steps: S1: Using the phenolic drug acting on cholinesterase as a starting material, carrying out a hydroxymethylation reaction on it to obtain compound B.

[0023] In a specific embodiment, the hydroxymethylation reagent used for the hydroxymethylation is any one or more of CH 3 I, CH 3 Br, CH 3 Cl, CH 4 among them.

[0024] In a specific embodiment, the phenolic drug acting on cholinesterase is dissolved in a first solvent, and a temperature-lowering reaction is carried out under alkaline conditions (pH > 10). The hydroxymethylation reagent is added dropwise under stirring, and after the addition is completed, a heat-preserving reaction is carried out. After the reaction is completed, compound B is obtained through treatment. Preferably, the volume-mass ratio of the phenolic drug dissolved in the organic solvent is 2 - 12 v / w (mL / g) (the first solvent is relative to the phenolic drug), and the further preferred volume-mass ratios are 2, 4, 6, 8, 9, 10 v / w (mL / g). Preferably, the dropping rate is 1 mL / min, the temperature is lowered to 0 - 5 °C, and the heat-preserving temperature is 20 - 30 °C. Preferably, the reaction solution after the reaction is poured into ice water to precipitate compound B. Preferably, through extraction, the organic phase is concentrated, ethyl acetate is added, and extraction and liquid separation are carried out.

[0025] S2: Carrying out a chlorination reaction on compound B to obtain compound C.

[0026] In a specific embodiment, the chlorination reagent used for the chlorination reaction is POCl 3 and / or PCl 5Optionally, dissolve Compound B in an organic solvent (5 V), add a chlorinating reagent (2.0 eq, relative to Compound B), and heat to 70 °C for reaction for 3 - 4 h. The preferred post-treatment is concentration, extraction, washing, and drying. Preferably, concentrate the filtrate by vacuum distillation, extract and separate with ethyl acetate, wash the organic phase with 1 mol / L HCl solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate and dry to obtain Compound C.

[0027] S3: Phosphorylate the Compound C to obtain Compound D.

[0028] In a specific embodiment, add acetonitrile (10 V), triethylamine (1.2 eq), and phosphoric acid (1.2 eq) to a three-necked flask, then add Compound C, and raise the temperature to 60 - 65 °C for reaction for 6 h. Concentrate the filtrate by vacuum distillation, extract with ethyl acetate, and dry the organic phase under reduced pressure to obtain the target product Compound D.

[0029] S4: Perform a salt-forming reaction on the Compound D to obtain the prodrug.

[0030] In a specific embodiment, the salt-forming reagent used for the salt-forming reaction is any one or more of sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, zinc salts, iron salts, and lithium salts. Optionally, when the salt-forming reagent is a sodium salt, the sodium salt is any one or more of sodium hydroxide, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate.

[0031] In a specific embodiment, add an organic solvent (2 V) to the three-necked flask in the specific embodiment of step S3. Preferably, adjust the pH (7.5 - 8.5) with 6 mol / L NaOH, precipitate a solid, cool the reaction to 0 - 5 °C and stir for reaction for 2 h, and filter and dry to obtain the target product.

[0032] It should be noted that the preparation methods in the above embodiments are only the preferred preparation methods of the present invention. Those skilled in the art can use other preparation methods in the prior art to prepare the prodrug when knowing the structural formula of the prodrug.

[0033] In a specific embodiment, taking the carvacrol prodrug shown in formula (4) as an example, the preparation method and principle of the carvacrol prodrug are as follows: (1) Using carvacrol as the starting material, dissolve carvacrol in a first solvent, slowly dropwise add a hydroxymethylating reagent under alkaline conditions, and perform a hydroxymethylation reaction to obtain Compound B.

[0034] (5) (2) Dissolve the compound B in a second solvent, add a chlorination reaction reagent, and carry out a chlorination reaction to obtain compound C.

[0035] (6) (3) Phosphorylate the compound C to obtain compound D, and then carry out a salt formation reaction on the compound D to obtain the carvacrol prodrug.

[0036] (7) In the above embodiments, the first solvent and the second solvent in steps (1) and (2) are respectively selected from any one or more of dichloromethane, chloroform, carbon tetrachloride, acetone, DMSO, DMF, tetrahydrofuran, and toluene; when carrying out the hydroxymethylation reaction in step (1), first react at 0 - 5 °C for 1.5 h, and then raise the temperature to 20 - 30 °C and react for 3 - 6 h; when carrying out the salt formation reaction in step (3), adjust the pH to 10 - 12 and react for 1 - 4 h; or preferably, adopt the method of double - base neutralization, first pre - neutralize with sodium carbonate to pH = 9.0, and then adjust with sodium hydroxide to pH = 10 - 12 and react for 1 - 4 h.

[0037] In the above embodiments, after the carvacrol prodrug (sodium phosphocarvacrol) is administered by injection, it decomposes under the action of alkaline phosphatase to generate carvacrol that can act on cholinesterase in cerebrospinal fluid. Carvacrol accumulates in the brain and can be rapidly metabolized after exerting its effect, with extremely small side effects on the body. Carvacrol has two metabolic pathways in the liver. One is that carvacrol undergoes a phase I oxidation reaction through the cytochrome P450 enzyme system, is hydroxylated to form 4 - hydroxycarvacrol, and then further forms a water - soluble metabolite under the action of sulfotransferase (SULT) and DT - diaphorase (NQO1) and is excreted from the body through the kidneys. The other is that without going through the phase I oxidation metabolic pathway, 70% of the carvacrol in the liver combines with glucuronic acid through uridine diphosphate glucuronosyltransferase (UGT) to form carvacrol glucuronide and then is excreted from the body through the kidneys.

[0038] On the other hand, the present invention also provides the application of the prodrug of the drug acting on cholinesterase described in any one of the above in the preparation of a cholinesterase inhibitor or a drug for treating central nervous system diseases.

[0039] In a specific embodiment, the prodrug is prepared into an injection preparation, and the injection preparation is a solution or a freeze - dried powder. In this embodiment, preparing the prodrug into an injection preparation can achieve the purpose of inhibiting cholinesterase or treating central nervous system diseases by intravenous injection.

[0040] In a specific embodiment, the solution agent comprises: a prodrug, a pH buffer, an osmotic pressure regulator, an antioxidant, and water for injection; the concentration of the prodrug is 0.01 - 10 mol / L, the pH adjustment range of the pH buffer is 4.5 - 9.0, the addition amount of the osmotic pressure regulator is 0.3 - 0.9%, the addition amount of the antioxidant is 0.0 - 0.2%, and the balance is water for injection. Optionally, the pH buffer is a sodium carbonate - sodium bicarbonate mixed solution, the osmotic pressure regulator is sodium chloride, and the antioxidant is citric acid. In this embodiment, the addition amounts of the osmotic pressure regulator and the antioxidant are both w / v (weight / volume), indicating the weight of the solute contained in a unit volume of the solution.

[0041] Example 1 A prodrug ([2-methyl-5-isopropylphenoxy]methylphosphate sodium) that acts on cholinesterase is prepared through the following steps: (1) Hydroxymethylation: Add carvacrol (10.0 g) and 50 mL of DMF to a 100 mL three-necked flask, stir to dissolve. Slowly add CH 3 I (molar ratio to carvacrol 2.0 eq), first react at 0 - 5 °C for 1.5 h, then stir and react at room temperature for 3 - 6 h. Monitor the reaction process by TLC (thin layer chromatography) until carvacrol is completely converted. After the reaction ends, dry under reduced pressure using a rotary evaporator to obtain a white solid compound B (2-methyl-5-isopropylphenoxymethanol) with a mass yield of 80%.

[0042] (2) Chlorination reaction: Dissolve the above product in DMF, add PCl 5 , heat to 70 °C and react for 3 - 4 h. After monitoring the completion of the reaction by TLC plate layer, concentrate the filtrate, add water and ethyl acetate to the remaining liquid, separate the organic phase, and wash the organic phase with 1 mol / L HCl solution, saturated NaHCO 3 solution, and saturated NaCl solution respectively. Combine the organic phases, dry with anhydrous sodium sulfate to obtain compound C with a mass yield of 74.38%.

[0043] (3) Phosphorylation reaction: Add acetonitrile (10 V), triethylamine (1.2 eq), and phosphoric acid (1.2 eq) to a three-necked flask, then add compound C, and react at 60 - 65 °C for 5 - 6 h. Monitor the reaction process by TLC until the intermediate is completely converted. After terminating the reaction, concentrate, add water and ethyl acetate to the remaining liquid to extract the organic phase, and concentrate the organic phase under reduced pressure to dryness for standby. The mass yield is 77.81%.

[0044] (4) Synthesis of prodrug (thymol sodium phosphate): Add absolute ethanol (2V) and the above product to a three-necked flask, adjust the pH to 10 - 12 with 6 mol / L NaOH, and react at 0 - 5 °C for 2 - 3 h. Recrystallize to obtain thymol sodium phosphate with high purity, and the mass yield is 78.3%.

[0045] Comparative Example 1 A prodrug of a drug ([2-methyl-5-isopropylphenoxy] sodium phosphate) has the structure shown in formula (8): (8) The [2-methyl-5-isopropylphenoxy] sodium phosphate is prepared by the following steps: (1) Chlorination reaction: Add thymol (10.0 g) and 50 mL of DMF to a 100 mL three-necked flask, stir to dissolve, add PCl 5 (1.0 eq), then stir and react at room temperature for 3 - 6 h. After monitoring the completion of the reaction by TLC plate layer, concentrate the filtrate, add water and ethyl acetate to the remaining liquid for extraction, and wash the organic phase separated by 1 mol / L HCl solution, saturated NaHCO 3 solution and saturated NaCl solution, combine the organic phases, dry with anhydrous sodium sulfate to obtain compound E.

[0046] (9) (2) Phosphorylation reaction: Add acetonitrile (10V), triethylamine (1.2 eq) and phosphoric acid (1.0 eq) to a three-necked flask, then add compound E, heat up to 60 - 65 °C and react for 6 h. After the reaction is completed, concentrate, add water and ethyl acetate to the remaining liquid for extraction, and concentrate the organic phase under reduced pressure to dryness to obtain compound F.

[0047] (10) (3) Synthesis of [2-methyl-5-isopropylphenoxy] sodium phosphate: Add absolute ethanol (2V) and compound F to a three-necked flask, adjust the pH to 10 - 12 with 6 mol / L NaOH, and react at 0 - 5 °C for 2 - 3 h. Recrystallize to obtain [2-methyl-5-isopropylphenoxy] sodium phosphate with high purity.

[0048] (11) Test Example 1 The in vitro enzymatic hydrolysis kinetics of [2-methyl-5-isopropylphenoxy] sodium phosphate prepared in Example 1 and [2-methyl-5-isopropylphenoxy] sodium phosphate prepared in Comparative Example 1 were compared: three groups of sample solutions with a concentration of 20 mg / mL (pH= 7.4 PBS buffer) were prepared in parallel, 0.08 U / mL alkaline phosphatase was added, and incubated at 37°C; sampling points were 0, 15, 30, 60, and 120 min, an equal volume of acetonitrile was added to terminate the reaction, and the supernatant was collected after centrifugation; HPLC method (C18 column, mobile phase: acetonitrile-0.1% formic acid water) was used to verify the release of carvacrol and calculate the enzymatic hydrolysis efficiency; after 30 min of enzymatic hydrolysis, the samples were stored at 4°C, 25°C, and 37°C, and the changes in carvacrol content were detected at 0, 2, 4, 8, and 24 h, respectively. The results are as follows: Figure 1 As shown. Figure 1 It can be seen that at 30 min of reaction, the enzymatic hydrolysis rates of the two were significantly different (P < 0.01), the enzymatic hydrolysis rate of Example 1 was 92.3% ± 1.5%, and the enzymatic hydrolysis rate of Comparative Example 1 was 73.2% ± 2.0%, which fully demonstrated that Example 1 can be efficiently enzymatically hydrolyzed to produce carvacrol.

[0049] Test Example 2 The Ellman colorimetric method was used to evaluate the inhibitory effects of [2-methyl-5-isopropylphenoxy] sodium methyl phosphate prepared in Example 1, [2-methyl-5-isopropylphenoxy] sodium phosphate prepared in Comparative Example 1, and carvacrol on acetylcholinesterase: a series of different concentrations of Example 1, Comparative Example 1, and carvacrol solutions (solvent: pH 7.4 PBS buffer) were prepared in parallel, 0.08 U / mL alkaline phosphatase, 0.08 U / mL acetylcholinesterase, and 5 mmol / L acetylcholine were added, and then the reaction was terminated after incubation at 37°C for 30 min. The enzyme activity of the control group and the inhibition group, the inhibition rate of the inhibitor at different concentrations, and the IC value of the inhibitor were calculated by measuring the change in absorbance. 50 Value, the result is Figure 2 As shown. Figure 2 It can be seen that Example 1 IC 50 Comparative Example 1 IC 50 Compared with the control group, the inhibition rate of Example 1 is higher, IC 50 = 25.09 μM, while the IC 50 = 42.67 μM. Compared with the drug itself, the inhibition rate of Example 1 is higher than that of the drug prodrug of Example 1. The inhibition rate of carvacrol at the same concentration (25.09 μM) is only 11%, which is much lower than the inhibition effect of Example 1.

[0050] As can be seen from Test Example 1 - Test Example 2, in the presence of phosphatase, the carvacrol prodrug prepared in Example 1, sodium [2-methyl-5-isopropylphenoxy]methyl phosphate, can be rapidly hydrolyzed into carvacrol, and has a more efficient acetylcholinesterase inhibitory effect than carvacrol. Also in the presence of phosphatase, the carvacrol prodrug prepared in Example 1, sodium [2-methyl-5-isopropylphenoxy]methyl phosphate, has a more efficient acetylcholinesterase inhibitory effect than sodium [2-methyl-5-isopropylphenoxy]phosphate prepared in Comparative Example 1. The effect of directly phosphorylating and modifying the phenolic hydroxyl group of carvacrol is poor, while modifying the phenolic hydroxyl group of carvacrol with the group shown in Formula (1) of the present invention can achieve a better acetylcholinesterase inhibitory effect.

[0051] It should be noted that the above-mentioned examples are only partial examples of the present invention. The prodrugs obtained by modifying the phenolic hydroxyl groups of eugenol and thymol with the group shown in Formula (1) have similar effects.

[0052] As described above, these are only representative examples of the present invention and do not impose any formal restrictions on the present invention. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, makes some modifications or alterations using the technical content disclosed above, and such embodiments are equivalent embodiments of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A prodrug of a drug acting on cholinesterase, characterized in that: The drug prodrug is obtained by modifying the phenolic hydroxyl group of the phenolic drug of cholinesterase with the group shown in formula (1): （1） In the formula: R is a metal ion, and the metal ion enables the prodrug to form a pharmaceutically acceptable salt.

2. The cholinesterase-acting drug prodrug according to claim 1, characterized in that: The phenolic drug acting on cholinesterase is eugenol, thymol or carvacrol.

3. The method for preparing a prodrug of a drug acting on cholinesterase as claimed in claim 1 or 2, characterized in that: The following steps are involved: S1: using the phenolic drug acting on cholinesterase as a starting material, subjecting it to a hydroxymethylation reaction to obtain compound B; S2: performing a chlorination reaction on the compound B to obtain a compound C; S3: phosphorylating the compound C to obtain compound D; S4: subjecting the compound D to a salt-forming reaction to obtain the drug prodrug.

4. The method for preparing a cholinesterase-acting drug prodrug according to claim 3, characterized in that: In step S1, the hydroxymethylation reagent used for hydroxymethylation is any one or more of CH3I, CH3Br, CH3Cl, and CH4.

5. The method for preparing the prodrug of the drug acting on cholinesterase according to claim 3, characterized in that: In step S2, the chlorination reagent used for the chlorination reaction is POCl3 and / or PCl5.

6. The method for preparing a cholinesterase-acting drug prodrug according to claim 3, characterized in that: In step S4, the salt-forming reagent used for the salt-forming reaction is any one or more of sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, zinc salt, iron salt, and lithium salt.

7. The method for preparing a prodrug of a drug acting on cholinesterase according to claim 6, characterized in that: When the salt-forming agent is a sodium salt, the sodium salt is any one or more of sodium hydroxide, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate.

8. Use of the cholinesterase-acting drug prodrug as claimed in claim 1 or 2 in the preparation of cholinesterase inhibitors or drugs for treating central nervous system diseases.

9. The use according to claim 8, characterized in that: The drug prodrug is prepared into an injection preparation, which is a solution or a lyophilized powder.

10. The use according to claim 9, characterized in that: The solution comprises: a drug prodrug, a pH buffer, an osmotic pressure regulator, an antioxidant and water for injection; the concentration of the drug prodrug is 0.01-10 mol / L, the pH adjustment range of the pH buffer is 4.5-9.0, the addition amount of the osmotic pressure regulator is 0.3-0.9%, the addition amount of the antioxidant is 0-0.2%, and the balance is the water for injection.

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