Paeonol carbamate compound, pharmaceutical preparation, preparation method and application

Abstract

The invention provides a paeonol carbamate compound, a pharmaceutical preparation, a preparation method and application, and relates to the field of compounds for preventing and treating Alzheimer's disease, Parkinson's disease and aging-related diseases, and the compound has a structure as shown in a formula I, or is a pharmaceutically acceptable salt of the structure as shown in the formula I. The paeonol carbamate compound, the pharmaceutical preparation, the preparation method and the application have the advantages that the paeonol carbamate compound has good butyrylcholine esterase resisting activity, and the paeonol carbamate compound has a good application prospect and good application potential in treatment of the Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to the field of compounds for preventing and treating Alzheimer's disease, Parkinson's disease and diseases related to aging, and in particular to a paeonol carbamate compound, a pharmaceutical preparation, a preparation method and an application thereof. Background Art

[0002] Paeonol is the main component isolated from the root bark of Paeonia lactiflora. Paeonol injection has been successfully used in China for nearly 50 years for inflammation / pain related indications. Currently, the dosage forms of paeonol approved by the China Food and Drug Administration include tablets, injections, and topical preparations such as ointments and adhesive plasters. So far, the clinical application of paeonol has mainly focused on anti-inflammatory effects. Research on other pharmacological activities of paeonol is developing rapidly and may play an important role in the future. Paeonol shows positive pharmacological effects in anti-inflammatory, neuroprotective, anti-tumor, and anti-cardiovascular disease.

[0003]

[0004] Rivastigmine is a reversible cholinesterase inhibitor, and clinical drugs containing a carbamate (–OCONH–) fragment can provide a preferred structural fragment for the treatment of mild to moderate dementia caused by AD or Parkinson's disease. Based on the cholinergic hypothesis, carbamate-like drugs are considered to be one of the main means of contemporary AD drug treatment by inhibiting inhibition.

[0005]

[0006] Since the modification of the skeleton structure of paeonol has potential significance, the carbamate structure of rivastigmine is introduced into the parent core structure of paeonol, and the two are combined and fused to design paeonol carbamate compounds that also have broad biological activity. Based on the above content, a paeonol carbamate compound, a pharmaceutical preparation, a preparation method and an application are proposed. Summary of the invention

[0007] The purpose of the present invention is to provide a paeonol carbamate compound, a pharmaceutical preparation, a preparation method and an application thereof, which has good anti-butyrylcholinesterase activity and shows good application prospect and potential in the treatment of Alzheimer's disease.

[0008] To achieve the above object, the present invention provides a paeonol carbamate compound, wherein the compound is a compound having a structure shown in Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1 and R2 are selected from H, (C1-C6) alkyl, heteroaryl, substituted aryl, or a mixture of one or more substituents, and the substituents in the substituted aryl are selected from halo, cyano, nitro, alkoxy, or alkanethio;

[0011]

[0012] Alternatively, NR1R2 is selected from one or more substituents selected from 3-7 membered cyclic amines, heterocyclic amines containing N, O or S, and the substituents in the substituted aryl group are selected from halo, cyano, alkoxy or alkanethio;

[0013]

[0014] Preferably, R1 and R2 are selected from one or more mixed substituents of H, (C1-C3) alkyl, pyridyl, furyl, thienyl, benzyl, substituted phenyl, and the substituents in the substituted aryl are selected from halo, cyano, nitro, (C1-C3) alkoxy or alkanethio.

[0015] Preferably, the compound is a compound of formula II or III or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Preferably, the compound is a compound having a structure as shown in Table 1-14 below or a pharmaceutically acceptable salt thereof:

[0018] The compounds described in Table 1 are compounds with structures shown in Tables 1-14 below or their pharmaceutically acceptable salts

[0019]

[0020]

[0021] The invention discloses an application of a paeonol carbamate compound in the preparation of butyrylcholinesterase inhibitor drugs.

[0022] A paeonol carbamate pharmaceutical preparation, wherein the active ingredient of the pharmaceutical preparation contains paeonol carbamate compounds.

[0023] Preferably, the dosage of the active ingredient in the pharmaceutical preparation is 0.01-500 mg / kg, and the pharmaceutical preparation can be made into various pharmaceutical dosage forms such as tablets, capsules, lozenges, injections, suspensions, suppositories or ointments by adding excipients acceptable in pharmacy; wherein the excipients include excipients and carriers, the excipients include one or more combinations of calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, and the carriers include one or more combinations of diluents, disintegrants, binders and lubricants.

[0024] A paeonol aminobamate pharmaceutical preparation is used in the preparation of a drug for treating or preventing aging and Alzheimer's disease.

[0025] A method for preparing a paeonol carbamate compound comprises the following steps:

[0026] (1) reacting an amine compound with triphosgene in an ice bath to prepare an acyl chloride intermediate;

[0027] (2) subjecting the acyl chloride intermediate of step (1) to a substitution reaction with paeonol under alkaline conditions to obtain paeonol carbamate compounds.

[0028] Preferably, the reaction process of steps (1) and (2) is as follows:

[0029]

[0030] Where R is H or

[0031] The specific preparation method includes the following steps, but is not limited thereto:

[0032] S1. Within half an hour, 5 mL CH2Cl2 solution of 30.0 mmol amine compound was added dropwise to 30 mL CH2Cl2 solution of 60.0 mmol sodium bicarbonate and 20.0 mmol triphosgene at -10°C, and the reaction mixture was warmed to room temperature and stirred for 6-8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to obtain the corresponding carbamoyl chloride.

[0033] S2, add the corresponding 6.0mmol carbamoyl chloride to a mixture of 6.0mmol anhydrous K2CO3, 2.0mmol 4-DMAP and 5.0mmol paeonol in 5mL MeCN. Heat the reaction mixture to 60-65°C and stir for 5-10 hours under argon, monitor the reaction by TLC, evaporate the solvent under reduced pressure after the reaction is completed, add 20mL water to the residue, and extract the mixture with 2×30mL CH2Cl2, wash the combined organic phase with 20mL 5% NaOH solution, 20mL 5% HCl solution and 25mL saturated sodium chloride aqueous solution, dry with anhydrous Na2SO4 and filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel flash column chromatography (mobile phase 2:1 CH2Cl2-EtOAc) to obtain paeonol carbamate compounds.

[0034] Preferably, the amine compound in step (1) is any one of the following amines: morpholine, piperidine, pyrrole, dimethylamine, diethylamine, methylethylamine, N-methylbenzylamine, N-methyl-3-fluorobenzylamine, N-methyl-3-chlorobenzylamine, N-methyl-3-bromobenzylamine, N-methyl-4-fluorobenzylamine, N-methyl-4-chlorobenzylamine, N-methyl-4-bromobenzylamine, etc.

[0035] Therefore, the present invention adopts the above-mentioned paeonol carbamate compound, pharmaceutical preparation, preparation method and application, and the technical effects are as follows:

[0036] (1) The preparation process is simple and easy to operate;

[0037] (2) It has good anti-butyrylcholinesterase activity and shows good application prospects and potential in the treatment of Alzheimer's disease. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further illustrated by the following examples.

[0039] Unless otherwise defined, technical or scientific terms used in the present invention shall have the common meanings understood by one having ordinary skills in the field to which the present invention belongs.

[0040] Example 1

[0041] Preparation of intermediate 1-II in the preparation process of paeonol carbamate compounds.

[0042]

[0043] The steps include:

[0044] In half an hour, a solution of intermediate 1-I dimethylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 6-8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 1-II.

[0045] Preparation of 2-acetyl-5-methoxyphenyl dimethylcarbamate (structure as shown in Formula 1):

[0046]

[0047] Intermediate 1-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (mobile phase 2:1 CH2Cl2-EtOAc) to give a white solid, 2-acetyl-5-methoxyphenyl dimethylcarbamate.

[0048] Structural data characterization:

[0049] 1 H NMR(400MHz, CDCl3) δ7.80(d,J=8.8Hz,1H),6.79(dd,J=8.8,2.6Hz,1H),6.63(dd,J=8.9,2.6Hz,1H),3 .84(s,3H),3.48(m,2H),3.07(d,J=43.6Hz,3H),2.51(s,3H),1.30–1.21(m,3H).HRMS(ESI):m / z[M+H] + Calculate for C 12 H 16 NO4:238.1079; found:238.1072.

[0050] Example 2

[0051] Preparation of intermediate 2-II in the preparation process of paeonol carbamate compounds.

[0052]

[0053] The steps include:

[0054] Over half an hour, a solution of intermediate 2-I methylethylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 2-II.

[0055] Preparation of 2-acetyl-5-methoxyphenylethyl (methyl) carbamate (structure as shown in Formula 2):

[0056]

[0057] Intermediate 2-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenylethyl (methyl)carbamate as a white solid.

[0058] Structural data characterization:

[0059] 1H NMR (400MHz, CDCl3) δ7.80 (d, J=8.8Hz, 1H), 6.79 (dd, J=8.8, 2.6Hz, 1H), 6.63 (dd, J=8.9, 2.6Hz, 1H), 3.84 (s, 3H), 3.48(dq,J=44.8,7.1Hz,2H),3.07(d,J=43.6Hz,3H),2.51(s,3H),1.30–1.21(m,3H).12.51.HRMS(ESI):m / z[M+H] + Calculate for C 13 H 18 NO4:252.1236; found:252.1229.

[0060] Example 3

[0061] Preparation of intermediate 3-II in the preparation process of paeonol carbamate compounds.

[0062]

[0063] The steps include:

[0064] In half an hour, a solution of intermediate 3-I pyrrolidine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 6-8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 3-II.

[0065] Preparation of 2-acetyl-5-methoxyphenylpyrrolidine-1-carboxylate (structure as shown in Formula 3):

[0066]

[0067] Intermediate 3-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenylpyrrolidine-1-carboxylate as a white solid.

[0068] Structural data characterization:

[0069] 1 H NMR(400MHz, CDCl3) δ7.80(d,J=8.8Hz,1H),6.79(dd,J=8.8,2.6Hz,1H),6.63(dd,J=8.9,2.6Hz,1H),3 .84(s,3H),3.48(m,2H),3.07(d,J=43.6Hz,3H),2.51(s,3H),1.30–1.21(m,3H).HRMS(ESI):m / z[M+H] + Calculate for C 12 H 16 NO4:238.1079; found:238.1072.

[0070] Example 4

[0071] Preparation of intermediate 4-II in the preparation process of paeonol carbamate compounds.

[0072]

[0073] The steps include:

[0074] A solution of intermediate 4-I thiazolidine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 4-II.

[0075] Preparation of 2-acetyl-5-methoxyphenylthiazolidine-3-carboxylate (structure as shown in formula 4):

[0076]

[0077] Intermediate 4-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenylthiazolidine-3-carboxylate as a white solid.

[0078] Structural data characterization:

[0079] 1 H NMR(500MHz, CDCl3)δ7.73(m,J=9.1,2.5Hz,1H),6.73(m,J=8.7,2.4Hz,1H),6.59(q,J=2.3Hz,1H),4 .56(d,J=58.1Hz,2H),3.90–3.72(m,5H),3.12–2.93(m,2H),2.49–2.28(m,3H).HRMS(ESI):m / z[M+H] + Calculate for C 13 H 16 NO4S:282.3340; found:282.3342.

[0080] Example 5

[0081] Preparation of intermediate 5-II in the preparation process of paeonol carbamate compounds.

[0082]

[0083] The steps include:

[0084] A solution of intermediate 5-I piperidine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 5-II.

[0085] Preparation of 2-acetyl-5-methoxyphenylpyrrolidine-1-carboxylate (structure as shown in Formula 5):

[0086]

[0087] Intermediate 5-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenylpiperidine-1-carboxylate as a white solid.

[0088] Structural data characterization:

[0089] 1 H NMR (400MHz, CDCl3) δ7.81 (d, J=8.8Hz, 1H), 6.79 (dd, J=8.8, 2.5Hz, 1H), 6.63 (d, J=2.6Hz, 1H),3.83(s,3H),3.70–3.45(m,4H),2.52(s,3H),1.68(s,6H).HRMS(ESI):m / z[M+H]+calcd for C 15 H20 NO4:278.1392; found:278.1385.

[0090] Example 6

[0091] Preparation of intermediate 6-II in the preparation process of paeonol carbamate compounds.

[0092]

[0093] The steps include:

[0094] A solution of intermediate 6-I methylpiperidine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 6-II.

[0095] Preparation of 2-acetyl-5-methoxyphenyl 4-methylpiperidine-1-carboxylate (structure as shown in Formula 6):

[0096]

[0097] Intermediate 6-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give a white solid, 2-acetyl-5-methoxyphenyl 4-methylpiperidine-1-carboxylate.

[0098] Structural data characterization:

[0099] 1H NMR (500MHz, CDCl3) δ7.73(d,J=8.8Hz,1H),6.72(dd,J=8.8,2.5Hz,1H),6.56(d,J=2.5Hz,1H),4.17(m,2H),3.77(s,3H),3.02–2. 77(m,2H),2.44(s,3H),1.65(d,J=12.8Hz,2H),1.58–1.51(m,1H),1.25–1.15(m,2H),0.93(d,J=6.6Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 16 H 22 NO4:292.1549; found:292.1543.

[0100] Example 7

[0101] Preparation of intermediate 7-II in the preparation process of paeonol carbamate compounds.

[0102]

[0103] The steps include:

[0104] A solution of intermediate 7-1N-methylbenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 7-II.

[0105] Preparation of 2-acetyl-5-methoxyphenyl benzyl (methyl) carbamate (structure as shown in formula 7):

[0106]

[0107] Intermediate 7-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenylbenzyl (methyl)carbamate as a white solid.

[0108] Structural data characterization:

[0109] 1 H NMR (500MHz, CDCl3) δ7.74(t,J=8.5Hz,1H),7.31(dd,J=8.7,5.5Hz,4H),7.26–7.22(m,1H),6.73(m,1H),6.57(dd,J=38.6,2. 5Hz,1H),4.58(d,J=70.1Hz,2H),3.78(d,J=9.9Hz,3H),2.96(d,J=34.0Hz,3H),2.44(d,J=12.4Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 18 H 20 NO4:314.1392; found:314.1386.

[0110] Example 8

[0111] Preparation of intermediate 8-II in the preparation process of paeonol carbamate compounds.

[0112]

[0113] The steps include:

[0114] A solution of intermediate 8-1N-methyl-4-chloroaniline (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 8-II.

[0115] Preparation of 2-acetyl-5-methoxyphenyl (4-chlorophenyl) (methyl) carbamate (structure as shown in formula 8):

[0116]

[0117] Intermediate 8-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated sodium chloride aqueous solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give a pale white solid as 2-acetyl-5-methoxyphenyl(4-chlorophenyl)(methyl)carbamate.

[0118] Structural data characterization:

[0119] 1 H NMR(500MHz,CDCI3)δ7.80(d,J=8.7Hz,1H),7.48–7.31(m,4H),6.79(d,J=8.8Hz ,1H),6.60(s,1H),3.83(s,3H),3.41(s,3H),2.49(s,3H).HRMS(ESI):m / z[M+H] + Calculate for C 17 H 17 ClNO4:334.0846; found:334.0842.

[0120] Example 9

[0121] Preparation of intermediate 9-II in the preparation process of paeonol carbamate compounds.

[0122]

[0123] The steps include:

[0124] A solution of intermediate 9-1N-methyl-4-chlorobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 8-II.

[0125] Preparation of 2-acetyl-5-methoxyphenyl (4-chlorobenzyl) (methyl) carbamate (structure as shown in formula 8):

[0126]

[0127] Intermediate 8-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated sodium chloride aqueous solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl (4-chlorobenzyl) (methyl) carbamate as a white solid.

[0128] Structural data characterization:

[0129] 1H NMR (500MHz, CDCl3) δ7.82(d,J=8.4Hz,1H),7.35(dd,J=12.7,6.9Hz,4H),6.81(dd,J=8.4,3.3Hz,1H),6.70–6.58(m,1 H),4.61(d,J=73.6Hz,2H),3.84(d,J=6.8Hz,3H),3.02(d,J=42.9Hz,3H),2.51(d,J=5.9Hz,3H).HRMS(ESI):m / z[M+H] + calcdfor C 18 H 19 ClNO4:348.1003; found:348.0998.

[0130] Example 10

[0131] Preparation of intermediate 10-II in the preparation process of paeonol carbamate compounds.

[0132]

[0133] The steps include:

[0134] A solution of the intermediate 8-1N-methyl-4-bromobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 10-II.

[0135] Preparation of 2-acetyl-5-methoxyphenyl (4-bromobenzyl) (methyl) carbamate (structure as shown in formula 10):

[0136]

[0137] Intermediate 10-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl (4-bromobenzyl) (methyl) carbamate as a white solid.

[0138] Structural data characterization:

[0139] 1 H NMR (500MHz, CDCl3) δ7.81(t,J=8.3Hz,1H),7.56–7.48(m,2H),7.28(d,J=6.1Hz,2H),6.81(m,1H),6.64(dd,J=38.9,2.6H z,1H),4.60(d,J=73.6Hz,2H),3.85(d,J=7.2Hz,3H),3.02(d,J=41.9Hz,3H),2.52(d,J=5.9Hz,3H).HRMS(ESI):m / z[M+H] + calcdfor C 18 H 19 BrNO4:392.0497; found:392.0492.

[0140] Embodiment 11

[0141] Preparation of intermediate 11-II in the preparation process of paeonol carbamate compounds.

[0142]

[0143] The steps include:

[0144] In half an hour, a solution of intermediate 11-1N-methyl-4-fluorobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 6-8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 11-II.

[0145] Preparation of 2-acetyl-5-methoxyphenyl (4-fluorobenzyl) (methyl) carbamate (structure as shown in formula 11):

[0146]

[0147] Intermediate 11-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl(4-fluorobenzyl)(methyl)carbamate as a white solid.

[0148] Structural data characterization:

[0149] 1 H NMR (500MHz, CDCl3) δ7.81(dd,J=8.8,6.8Hz,1H),7.37(m,2H),7.06(dt,J=12.8,8.6Hz,2H),6.80(m,1H),6.65(dd,J=31.8,2 .6Hz,1H),4.61(d,J=72.3Hz,2H),3.83(d,J=5.4Hz,3H),3.01(d,J=46.0Hz,3H),2.51(d,J=4.5Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 18 H 19FNO4:332.1298; found:332.1292.

[0150] Example 12

[0151] Preparation of intermediate 12-II in the preparation process of paeonol carbamate compounds.

[0152]

[0153] The steps include:

[0154] A solution of intermediate 12-1N-methyl-3-fluorobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 12-II.

[0155] Preparation of 2-acetyl-5-methoxyphenyl (3-fluorobenzyl) (methyl) carbamate (structure shown in formula 12):

[0156]

[0157] Intermediate 12-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl(3-fluorobenzyl)(methyl)carbamate as a white solid.

[0158] Structural data characterization:

[0159] 1H NMR (500MHz, CDCl3) δ7.82(t,J=8.5Hz,1H),7.35(m,1H),7.19–7.08(m,2H),7.00(m,1H),6.81(ddd,J=8.8,4.9,2.5Hz,1H),6.65(dd,J =37.1,2.5Hz,1H),4.65(d,J=72.4Hz,2H),3.85(d,J=8.5Hz,3H),3.05(d,J=42.6Hz,3H),2.52(d,J=11.7Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 18 H 19 FNO4:332.1298; found:332.1292.

[0160] Example 13

[0161] Preparation of intermediate 13-II in the preparation process of paeonol carbamate compounds.

[0162]

[0163] The steps include:

[0164] A solution of intermediate 13-1N-methyl-2-fluorobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 13-II.

[0165] Preparation of 2-acetyl-5-methoxyphenyl (2-fluorobenzyl) (methyl) carbamate (structure as shown in formula 13):

[0166]

[0167] Intermediate 13-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl(2-fluorobenzyl)(methyl)carbamate as a white solid.

[0168] Structural data characterization:

[0169] 1 H NMR (500MHz, CDCl3) δ7.81(dd,J=8.8,4.7Hz,1H),7.48(m,1H),7.30(dd,J=12.3,4.5Hz,1H),7.18(m,1H),7.08(q,J=8.8Hz,1H),6.80(dd,J=8.8,4.9H z,1H),6.63(dd,J=40.0,2.6Hz,1H),4.71(d,J=65.5Hz,2H),3.84(d,J=8.3 Hz,3H),3.08(d,J=46.8Hz,3H),2.50(d,J=7.1Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 18 H 19 FNO4:332.1298; found:332.1292.

[0170] Embodiment 14

[0171] Preparation of intermediate 14-II in the preparation process of paeonol carbamate compounds.

[0172]

[0173] The steps include:

[0174] A solution of intermediate 14-1N-ethyl-4-chlorobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 14-II.

[0175] Preparation of 2-acetyl-5-methoxyphenyl (4-chlorobenzyl) (ethyl) carbamate (structure as shown in formula 14):

[0176]

[0177] Intermediate 14-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl (4-chlorobenzyl) (ethyl) carbamate as a white solid.

[0178] Structural data characterization:

[0179] 1 H NMR (400MHz, CDCl3) δ7.80(t,J=8.1Hz,1H),7.34(d,J=6.1Hz,4H),6.86–6.76(m,1H),6.62(d,J=36.3Hz,1H),4.61(d ,J=58.6Hz,2H),3.85(d,J=7.8Hz,3H),3.42(m,2H),2.52(d,J=10.3Hz,3H),1.27–1.19(m,3H).HRMS(ESI):m / z[M+H] + Calculate for C 19 H 21 ClNO4:341.4070; found:341.4070

[0180] Embodiment 15

[0181] Preparation of intermediate 15-II in the preparation process of paeonol carbamate compounds.

[0182]

[0183] The steps include:

[0184] A solution of intermediate 15-1N-methyl-3-bromobenzylamine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 15-II.

[0185] Preparation of 2-acetyl-5-methoxyphenyl (3-bromobenzyl) (methyl) carbamate (structure as shown in formula 15):

[0186]

[0187] Intermediate 15-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl (3-bromobenzyl) (methyl) carbamate as a white solid.

[0188] Structural data characterization:

[0189] 1H NMR (500MHz, CDCl3) δ7.82(t,J=8.5Hz,1H),7.54(d,J=4.3Hz,1H),7.44(t,J =7.2Hz,1H),7.35–7.30(m,1H),7.25(d,J=3.8Hz,1H),6.81(dt,J=9.1,3.0H z,1H),6.65(dd,J=37.4,2.5Hz,1H),4.62(d,J=72.3Hz,2H),3.85(d,J=6.5H z,3H),3.04(d,J=41.3Hz,3H),2.53(d,J=13.0Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 18 H 19 BrNO4:392.0497; found:392.0492.

[0190] Example 16

[0191] Preparation of intermediate 16-II in the preparation process of paeonol carbamate compounds.

[0192]

[0193] The steps include:

[0194] A solution of intermediate 16-I 1,2,3,4-tetrahydroisoquinoline (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 16-II.

[0195] Preparation of 2-acetyl-5-methoxyphenyl 3,4-tetrahydroisoquinoline-2(1H)-carboxylate (structure as shown in Formula 16):

[0196]

[0197] Intermediate 16-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl 3,4-tetrahydroisoquinoline-2(1H)-carboxylate as a white solid.

[0198] Structural data characterization:

[0199] 1 H NMR (500MHz, CDCl3) δ7.82(d,J=8.9Hz,1H),7.22–7.13(m,4H),6.81(dd,J=8.8,2.6Hz,1H),6.67(d,J=2.5Hz,1H),4.80(d,J=8 3.3Hz,2H),3.93(t,J=5.9Hz,1H),3.87–3.78(m,4H),2.98(dt,J=27.9,6.0Hz,2H),2.50(d,J=9.2Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 19 H 20 NO4:326.1392; found:326.1392.

[0200] Embodiment 17

[0201] Preparation of intermediate 17-II in the preparation process of paeonol carbamate compounds.

[0202]

[0203] The steps include:

[0204] A solution of intermediate 17-I 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C over half an hour. The reaction mixture was warmed to room temperature and stirred for 6–8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 17-II.

[0205] Preparation of 2-acetyl-5-methoxyphenyl 6,7-dimethoxy-3,4-tetrahydroisoquinoline-2(1H)-carboxylate (structure as shown in Formula 17):

[0206]

[0207] Intermediate 17-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl 6,7-dimethoxy-3,4-tetrahydroisoquinoline-2(1H)-carboxylate as a white solid.

[0208] Structural data characterization:

[0209] 1 HNMR(500MHz, CDCl3)δ7.83(d,J=8.8Hz,1H),6.81(dd,J=8.8,2.5Hz,1H),6.72–6.49(m,3H),4.7 4(d,J=84.4Hz,2H),3.95–3.75(m,11H),2.90(m,2H),2.51(d,J=8.4Hz,3H).HRMS(ESI):m / z[M+H] + Calculate for C 21 H 24 NO6:386.1604; found:386.1598.

[0210] Embodiment 18

[0211] Preparation of intermediate 18-II in the preparation process of paeonol carbamate compounds.

[0212]

[0213] The steps include:

[0214] In half an hour, a solution of intermediate 18-I 4-benzylpiperidine (30.00 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of sodium bicarbonate (5.04 g, 60 mmol) and triphosgene (5.94 g, 20 mmol) in CH2Cl2 (30 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 6-8 hours. The mixture was then filtered and the filtrate was evaporated under reduced pressure to give the corresponding 18-II.

[0215] Preparation of 2-acetyl-5-methoxyphenyl 4-benzylpiperidine-1-carboxylate (structure as shown in Formula 18):

[0216]

[0217] Intermediate 18-II (0.585 mmol) was added to a mixture of anhydrous K2CO3 (92 mg, 0.663 mmol), 4-DMAP (5.0 mg, 0.039 mmol) and paeonol (64 mg, 0.390 mmol) in 5 mL of MeCN. The reaction mixture was heated to 60–65 °C and stirred under argon for 5–10 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with 5% NaOH solution (20 mL), 5% HCl solution (20 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (mobile phase 2:1 CH2Cl2-EtOAc) to give 2-acetyl-5-methoxyphenyl 4-benzylpiperidine-1-carboxylate as a white solid.

[0218] Structural data characterization:

[0219] 1H NMR (500MHz, CDCl3) δ7.81(d,J=8.8Hz,1H),7.30(t,J=7.6Hz,2H),7.21–7.12(m,3H),6.79(dd,J=8.8,2.5Hz,1H),6.63(d,J=2.6Hz,1H),4.26(dd,J=4 2.3,13.4Hz,2H),3.84(s,3H),3.03–2.81(m,2H),2.61(d,J=6.9Hz,2H),2. 51(s,3H),1.74(d,J=13.9Hz,2H),1.40–1.23(m,3H).HRMS(ESI):m / z[M+Na] + Calculate for C 22 H 25 NO4Na:390.1681; found:390.1674.

[0220] Embodiment 19

[0221] The paeonol aminobamate compounds prepared in the above examples are used as active ingredients. According to conventional preparation methods of pharmaceutical preparations, the above compounds are prepared into one or more dosage forms of tablets, capsules, lozenges, injections, suspensions, suppositories, and ointments. The preparations include the active compounds themselves and pharmaceutically acceptable excipients, which are carriers or excipients.

[0222] Wherein, the dosage of the active compound in the above-mentioned pharmaceutical preparation is 0.01-500 mg / kg.

[0223] Among them, the excipient is calcium carbonate, calcium phosphate, sugar, starch, cellulose derivative, gelatin, vegetable oil or polyethylene glycol; the carrier is a diluent, disintegrant, binder or lubricant.

[0224] Anticholinesterase activity verification experiment:

[0225] In order to verify that the paeonol carbamate compounds disclosed in the present invention have anticholinesterase activity, the paeonol carbamate compounds (1-18) prepared in the above examples were selected for activity experiments.

[0226] 1. Experimental principle: The experiment adopts the modified Ellman method, using eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) and their corresponding substrates iodoacetylcholine iodide and thiobutyrylcholine iodide to simulate the in vivo reaction environment. 5,5'-ditiobis-2-nitrobenzoico (DTNB) combines with the enzyme-substrate complex to produce a yellow anion 5-thio-2-nitrobenzoic acid, and then the inhibitory activity of the compound on the enzyme is calculated by measuring the absorbance.

[0227] 2. The experimental steps are as follows:

[0228] (1) preparing the compound using a phosphate buffer at pH 8.0;

[0229] (2) The 48-well plate was divided into four groups: positive control group (donepezil + AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), experimental group (compound + AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), blank control group (AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), and background group (solvent + DTNB);

[0230] (3) Add 100 μL of compound (0.05, 0.5, 5, 50, 100 μM) solution to a 48-well plate, and replace the blank control wells and background wells with solvent;

[0231] (4) Add 100 μL of AChE / BuChE (0.18 U / mL) solution to a 48-well plate, except for the background wells which were replaced with solvent, and incubate at 37°C, 100 rpm on a constant temperature shaker for 20 min;

[0232] (5) Add 100 μL of solvent to the 48-well plate;

[0233] (6) Add 100 μL of iodoacetylcholine iodide / thiobutyrylcholine iodide (0.35 mM / 0.5 mM) solution to a 48-well plate, except for the background wells which were replaced with solvent;

[0234] (7) Add 100 μL of DTNB (0.35 mM) solution to a 48-well plate and incubate in a constant temperature shaker at 37°C and 100 rpm in the dark for 20 or 40 min;

[0235] (8) Use an ELISA reader to measure the absorbance at 410 nm and calculate the inhibition rate.

[0236] (9) The above experiments were repeated three times, and the results were analyzed using SPSS17.0 statistical analysis software to calculate the inhibition rate and IC50 .

[0237] 3. Experimental results: The experimental results are shown in Table 2:

[0238] Table 2: Statistical table of anticholinesterase data of corresponding numbered compounds in each example

[0239]

[0240] Note: IC 50 The value unit is: μmol / L, "na" means no activity.

[0241] As shown in Table 2, the raw materials have micromolar butyrylcholinesterase activity, and the paeonol carbamates provided in this embodiment also have good anti-butyrylcholinesterase activity, especially compounds 5 and 11 have nanomolar butyrylcholinesterase inhibitory activity, and the inhibitory activity is not only better than the marketed drug donepezil. Therefore, it shows good application prospects and potential in the treatment of Alzheimer's disease.

[0242] Therefore, the present invention adopts the above-mentioned paeonol aminobamate compound, pharmaceutical preparation, preparation method and application, which has good anti-butyrylcholinesterase activity, and shows good application prospects and potential in the treatment of Alzheimer's disease.

[0243] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A paeonol carbamate compound, characterized in that: The compound is a compound of the structure shown in Formula I or a pharmaceutically acceptable salt thereof: Wherein, R1 and R2 are selected from H, (C1-C6) alkyl, heteroaryl, substituted aryl, or a mixture of one or more substituents, and the substituents in the substituted aryl are selected from halo, cyano, nitro, alkoxy, or alkanethio; Alternatively, NR1R2 is selected from one or more substituents selected from 3-7 membered cyclic amines, heterocyclic amines containing N, O or S, and the substituents in the substituted aryl group are selected from halo, cyano, alkoxy or alkanethio; 2. A paeonol carbamate compound according to claim 1, characterized in that: R1 and R2 are selected from one or more mixed substituents of H, (C1-C3) alkyl, pyridyl, furyl, thienyl, benzyl, substituted phenyl, and the substituents of the substituted aryl are selected from halo, cyano, nitro, (C1-C3) alkoxy or alkanethio.

3. A paeonol carbamate compound according to claim 1, characterized in that: The compound is a compound of formula II or III or a pharmaceutically acceptable salt thereof:

4. A paeonol carbamate compound according to claim 1, characterized in that: The compound is a compound having a structure as shown in Table 1-14 below or a pharmaceutically acceptable salt thereof:

5. Use of the paeonol carbamate compound according to any one of claims 1 to 4 in the preparation of butyrylcholinesterase inhibitor drugs.

6. A paeonol carbamate pharmaceutical preparation, characterized in that: The active ingredient of the pharmaceutical preparation contains the paeonol carbamate compound as claimed in any one of claims 1 to 4.

7. Use of the paeonol aminobamate pharmaceutical preparation as claimed in claim 5 in the preparation of drugs for treating or preventing aging and Alzheimer's disease.

8. A method for preparing the paeonol carbamate compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) placing an amine compound in an ice bath under triphosgene to prepare an acyl chloride intermediate; (2) subjecting the acyl chloride intermediate of step (1) to a substitution reaction with paeonol under alkaline conditions to obtain paeonol carbamate compounds.

9. The method for preparing a paeonol carbamate compound according to claim 8, characterized in that: The reaction process of steps (1) and (2) is as follows:

10. The method for preparing a paeonol carbamate compound according to claim 8, characterized in that: The amine compound in step (1) is any one of the following amines: morpholine, piperidine, pyrrole, dimethylamine, diethylamine, methylethylamine, N-methylbenzylamine, N-methyl-3-fluorobenzylamine, N-methyl-3-chlorobenzylamine, N-methyl-3-bromobenzylamine, N-methyl-4-fluorobenzylamine, N-methyl-4-chlorobenzylamine, and N-methyl-4-bromobenzylamine.

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