An amide-substituted tryptophone derivative, a preparation method and application thereof

Abstract

The present application belongs to the technical field of pharmaceutical therapy, and particularly relates to an amide-substituted tryptophan ketone derivative, a preparation method and application thereof. The structural formula of the tryptophan ketone derivative is shown in formula (A) or formula (B). In the formula, n=1 or 2, and R is any one of dimethylamine group, diethylamine group, morpholine group, 1-methylpiperazine group, cyclopropylamine group and 4-hydroxypiperidyl group. The compound can selectively inhibit the activity of acetylcholinesterase, and has the potential to develop into a drug for treating Alzheimer's disease due to the abilities of self-aggregation and the like. 1‑42 ​

Description

Technical Field

[0001] This invention belongs to the field of pharmacotherapeutic technology, specifically relating to an amide-substituted tryptophanone derivative, its preparation method, and its application. Background Technology

[0002] Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system. Its clinical symptoms can be divided into two categories: memory impairment and cognitive impairment, accompanied by symptoms such as reduced self-care ability and mental impairment. Once patients show symptoms of AD, brain damage has often already occurred, and recovery becomes impossible. Therefore, AD has become the "fourth leading cause of death" threatening human health, after cardiovascular and cerebrovascular diseases, malignant tumors, and diabetes.

[0003] Numerous factors influence the development of Alzheimer's disease (AD), including family history, lifestyle habits, cardiovascular disease, education level, and conditions such as hypertension and diabetes. However, age and genetic factors play a crucial role. The pathogenesis of AD involves abnormalities in multiple pathways and processes, with interactions and mutual influences between different mechanisms. Currently, its pathogenesis is not fully understood, and there is no unified understanding. Several hypotheses exist, including the cholinergic hypothesis, the amyloid cascade hypothesis, the oxidative stress hypothesis, the tau protein hypothesis, the metal ion hypothesis, and the inflammation and mitochondrial dysfunction hypothesis.

[0004] The cholinergic hypothesis was the earliest hypothesis used to explain the pathogenesis of Alzheimer's disease (AD). This hypothesis posits that memory loss and cognitive impairment in AD patients are caused by decreased acetylcholine levels. Therefore, inhibiting cholinesterase's hydrolysis of acetylcholine can lead to synaptic accumulation and increased acetylcholine levels, ensuring normal transmission of nerve signals and thus improving learning and memory. Currently, a series of drugs have been developed for the clinical treatment of AD, including tacrine, donepezil, galantamine, and rivastigmine. However, tacrine has been withdrawn from clinical use due to hepatotoxicity issues. These neurotransmitter modulators can improve patients' cognitive abilities and daily living skills, but they cannot fundamentally improve the clinical state of the disease or halt its progression. Therefore, the development of AD treatment drugs has become a key focus in the pharmaceutical and medical fields, and the research and development of more effective AD treatments is urgently needed.

[0005] Tryptophanone is an indolequinazoline alkaloid widely found in cyanogenic plants such as Polygonum tinctorium, Strobilanthes bidentata, and Isatis tinctoria. Currently, there are some reports on research on tryptophanone and its derivatives both domestically and internationally. It has been found that it has strong inhibitory effects on fungi, bacteria, parasites, and various tumor cells, showing high development value. Patent CN114874220A discloses the application of 8-aminobenzenesulfonamide-substituted tryptophanone derivatives in the preparation of drugs to inhibit AChE and in the treatment of Alzheimer's disease (AD), but the synthesis of this compound is relatively complex.

[0006] Providing a compound that is simple to synthesize and effective in inhibiting AchE provides a new drug for the treatment of AD, which is of positive significance. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention first provides an amide-substituted tryptamine ketone derivative, the structural formula of which is shown in formula (A) or formula (B):

[0008]

[0009] In the formula, n = 1 or 2, and R is any one of dimethylamino, diethylamino, morpholino, 1-methylpiperazinyl, cyclopropylamino, and 4-hydroxypiperidinyl.

[0010] This invention provides a method for preparing amide-substituted tryptamine ketone derivatives as described above. The method for preparing tryptamine ketone derivatives with the structural formula shown in formula (A) includes the following steps:

[0011] S1. Under nitrogen protection, indigo anhydride reacts with indigo in a one-pot reaction with triethylamine and toluene to yield tryptamine ketone;

[0012] S2. Nitrate tryptophanone under HNO3 conditions to obtain 8-nitrotryptophanone;

[0013] S3,8-nitrotryptamine ketone is reduced by SnCl2 and HCl to give 8-aminotryptamine ketone;

[0014] S4,8-amino-tryptamine ketone reacts with chloroacetyl chloride or chloropropionyl chloride to give the corresponding acylated products;

[0015] S5. The acylated products prepared in step S4 are reacted with amines having the corresponding R groups in acetonitrile solution. The purified products are amide-substituted tryptamine ketone derivatives having the structure shown in formula (A). The R group is any one of dimethylamino, diethylamino, morpholino, 1-methylpiperazinyl, cyclopropylamino, and 4-hydroxypiperidinyl.

[0016] The above synthesis path is represented as follows:

[0017]

[0018] I. Indigo anhydride and indigo undergo a dehydration condensation reaction under the protection of triethylamine and nitrogen to give compound a (tryptamine ketone); II. Compound a undergoes a nitration reaction in an ice-water bath of concentrated sulfuric acid and concentrated nitric acid to generate compound b (8-nitrotryptamine ketone); III. Compound b and stannous chloride dihydrate are added to an ethanol-hydrochloric acid solution and undergo a hydrogenation reduction reaction to give compound c (8-aminotryptamine ketone); IV. After purification by column chromatography, compound c is reacted with chloroacetyl chloride and chloropropionyl chloride under acetone and anhydrous potassium carbonate conditions to give compounds d and e, respectively; V. Compounds d and e react with amines having various substituents R (75°C) and are purified by column chromatography to give compounds f1-g6, wherein the R group is any one of dimethylamino, diethylamino, morpholino, 1-methylpiperazinyl, cyclopropylamino, or 4-hydroxymethylpiperidinyl.

[0019] The method for preparing tryptophan ketone derivatives with the structure shown in formula (B) includes the following steps:

[0020] S1. Indomethacin anhydride was reacted with concentrated H2SO4 in the presence of KNO3 to yield the precursor of the compound;

[0021] S2. The precursor of the compound reacts with indigo under the protection of triethylamine and nitrogen to undergo a dehydration condensation reaction to give 2-nitrotryptamine ketone;

[0022] S3.2-nitrotryptamine and stannous chloride dihydrate were added to an ethanol-hydrochloric acid solution and then hydrogenated to reduce the 2-aminotryptamine.

[0023] S4,2-amino-tryptamine ketone reacts with chloroacetyl chloride or chloropropionyl chloride to give the corresponding acylated products;

[0024] S5. The acylated products prepared in step S4 are reacted with amines having the corresponding R groups in acetonitrile solution. The purified products are amide-substituted tryptamine ketone derivatives having the structure shown in formula (B). The R group is any one of dimethylamino, diethylamino, morpholino, 1-methylpiperazinyl, cyclopropylamino, and 4-hydroxypiperidinyl.

[0025] The above synthesis path is represented as follows:

[0026]

[0027] VI. In the presence of KNO3, in concentrated H2SO4, indigo anhydride is reacted to give compound h; I. Compound h (precursor) reacts with indigo under the protection of triethylamine and nitrogen to give compound i (2-nitrotryptamine); III. Compound i and stannous chloride dihydrate are added to ethanol-hydrochloric acid solution and hydrogenated to give compound j (2-aminotryptamine); IV. Compound j is purified by column chromatography and reacted with chloroacetyl chloride and chloropropionyl chloride to give compounds k and l, respectively; V. Compounds k and l react with amines having various substituents R (75°C) and purified by column chromatography to give compounds m1-n6, wherein the R group is any one of dimethylamino, diethylamino, morpholino, 1-methylpiperazinyl, cyclopropylamino, or 4-hydroxymethylpiperidinyl.

[0028] The preparation route is primarily for illustrative purposes and not for limiting the invention.

[0029] Preferably, in step S5, the solvent for the reaction is acetonitrile, the reaction temperature is 75°C, and the stirring time is 4-6 hours.

[0030] This invention provides the use of the amide-substituted tryptamine derivatives as described above in the preparation of acetylcholinesterase inhibitors.

[0031] This invention provides the use of the amide-substituted tryptamine ketone derivatives as described above in the preparation of medicaments for treating Alzheimer's disease.

[0032] The present invention also provides an acetylcholinesterase inhibitor or a medicament for treating Alzheimer's disease, said medicament containing a pharmaceutically effective dose of the tryptophan derivative as described above.

[0033] Preferably, the drug further comprises a pharmaceutically acceptable carrier.

[0034] Preferably, the pharmaceutically acceptable carrier includes one or more excipients with functions such as excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents; such as starch, lipids, waxes, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.

[0035] Preferably, the drug is any one of injection, tablet, pill, capsule, suspension or emulsion.

[0036] The beneficial effects of this invention are as follows:

[0037] 1. The amide-substituted tryptophanone derivatives involved in this invention have a selective inhibitory effect on AChE activity, indicating that these compounds have the potential to be developed into effective AChE inhibitors.

[0038] 2. The amide-substituted tryptophan derivatives involved in this invention can inhibit the self-aggregation of β-amyloid protein, indicating that such compounds have the potential to be developed into effective treatments for Alzheimer's disease.

[0039] 3. The compound n1 involved in this invention significantly improves the learning and memory abilities and behaviors of AD animal models in terms of space and orientation, and its effect is superior to donepezil, a first-line clinical drug, indicating that this type of compound has the potential to be developed into an effective treatment for Alzheimer's disease.

[0040] 4. The compounds involved in this invention have the potential to be developed into drugs for the treatment of Alzheimer's disease. Attached Figure Description

[0041] Figure 1 The figure shows the results of TEM observation on the inhibitory effect of the compound on Aβ aggregation. In the figure, A represents Aβ. 1-42 Incubate alone for 0 hours; B is Aβ 1-42 Incubate alone for 48 hours; C is Aβ 1-42 Incubate with compound n1 (100 μM) for 48 hours; D is Aβ. 1-42 Incubate with donepezil (100 μM) for 48 hours; E represents Aβ. 1-42 Incubate with curcumin (20 μM) for 48 hours.

[0042] Figure 2 The protective effect of compound n1 against H2O2-induced PC12 cell death;

[0043] Figure 3-8 The results of the Morris water maze test in mice induced by scopolamine, using compound n1, are shown.

[0044] Figure 3 The graph shows the effect of different concentrations of compound n1 on mouse body weight during a 7-day dosing period.

[0045] Figure 4 Results showing the difference in swimming speed between the drug group and the normal group;

[0046] Figure 5 This indicates the time it took for mice in the drug group and the normal group to find the plateau;

[0047] Figure 6 The results show the number of crossovers between the drug group and the normal group mice on the virtual platform after the platform was removed;

[0048] Figure 7 The results show the time spent in the target quadrant by mice in the drug group and the normal group after the platform was removed.

[0049] Figure 8This is a representative trajectory diagram of mice in the Morris water maze test. As can be seen from the diagram, after the platform was removed, except for the normal group, the mice treated with a dose of 20 mg / kg took significantly less time to enter the platform quadrant and entered the area more frequently than the model group. Detailed Implementation

[0050] Unless otherwise stated, the terms used herein have the meanings commonly understood by those skilled in the art.

[0051] The technical solution of the present invention will be described in more detail below with reference to the embodiments.

[0052] Example 1

[0053] Synthesis of compound f1

[0054]

[0055] Compound d (339 mg, 1 mM) was dissolved in 30 mL of acetonitrile, followed by the addition of dimethylamine (54 mg, 1.2 mM) (R group being dimethylamino) and triethylamine (101 mg, 1.2 mM), and refluxed at 75 °C for 8–12 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed. Compound f1 was purified by column chromatography using dichloromethane:methanol (50:1) to give a yellow solid in 75% yield. 1 H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.32(d,J=8.7Hz,1H),8.28–8.22(m,2H),7.97(dd,J=8 .8,2.3Hz,1H),7.91(d,J=4.1Hz,2H),7.70(dq,J=8.1,4.3Hz,1H),3.11(s,2H),2.29(s,6H). 13 C NMR(126MHz,DMSO-d6)δ182.81,169.76,157.78,146.83,145.71,141.74,138.00,135 .50,130.36,130.29,128.45,127.28,123.75,122.88,117.75,115.46,63.69,45.84.

[0056] Example 2

[0057] Synthesis of compound f2

[0058]

[0059] The method is the same as in Example 1, except that the R group is replaced with a diethylamino group, yielding a yellow solid with a yield of 72%.1 HNMR (600MHz, DMSO-d6) δ10.05(s,1H),8.39(d,J=8.7Hz,1H),8.32(dt,J=7.7,1.1Hz,1H),8.27(d,J=2.3Hz,1H),8.04(dd,J=8 .7,2.3Hz,1H),7.97–7.91(m,2H),7.74(ddd,J=8.1,5.6,2.8Hz,1H),3.21(s,2H),2.62(q,J=7.1Hz,4H),1.04(t,J=7.1Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ181.84,170.04,156.80,145.83,144.76,140.81,136.69,134.45 ,129.30,129.24,127.42,126.25,122.75,121.96,116.76,114.44,56.75,47.25,11.25.

[0060] Example 3

[0061] Synthesis of compound f3

[0062]

[0063] The method is the same as in Example 1, except that the R group is replaced with a morpholino group, yielding a yellow solid with a yield of 71%. 1 HNMR(500MHz,DMSO-d6)δ10.12(s,1H),8.31(d,J=8.6Hz,1H),8.25(d,J=7.9Hz,1H),8.20(d,J=2.3Hz,1H ),7.97–7.88(m,3H),7.74–7.66(m,1H),3.66(t,J=4.5Hz,4H),3.17(s,2H),2.52(dd,J=14.1,3.3Hz,4H). 13 C NMR (126MHz, DMSO-d6) δ182.78,169.12,157.76,146.81,145.68,141.75,137.85,135.49 ,130.36,130.30,128.41,127.27,123.72,122.88,117.78,115.47,66.49,62.43,53.64.

[0064] Example 4

[0065] Synthesis of compound f4

[0066]

[0067] The method is the same as in Example 1, except that the R group is replaced with 1-methylpiperazine, yielding a yellow solid with a yield of 75%. 1 H NMR (500MHz, DMSO-d6) δ10.11(s,1H),8.34(d,J=8.6Hz,1H),8.27(d,J=7.9Hz,1H),8.21(d,J=2.2Hz,1 H),7.96–7.90(m,3H),7.71(dt,J=8.2,4.2Hz,1H),3.16(s,2H),2.55(s,4H),2.46(s,4H),2.22(s,3H). 13 C NMR (126MHz, DMSO-d6) δ182.83,169.34,157.81,146.84,145.73,141.80,137.85,135.52,13 0.36,130.32,128.42,127.30,123.75,122.94,117.83,115.45,62.04,54.75,52.84,45.90.

[0068] Example 5

[0069] Synthesis of compound f5

[0070]

[0071] The method is the same as in Example 1, except that the R group is replaced with a cyclopropylamino group, yielding a yellow solid with a yield of 61%. 1 HNMR(500MHz,DMSO-d6)δ9.98(s,1H),8.28(d,J=5.2Hz,1H),8.24(dd,J=4.8,0.9Hz,1H),8.12(d,J=1.3Hz,1H),7.88–7.83(m,1H),7.76(d, J=4.8Hz,1H),7.68–7.61(m,2H),4.53–4.29(m,1H),3.35(s,2H),2.19(t,J=2.1Hz,1H),0.39(dd,J=3.9,1.6Hz,2H),0.32(q,J=1.9Hz,2H). 13C NMR (126MHz, DMSO-d6) δ171.19,158.25,151.14,146.90,145.12,137.72,135.82,134.9 9,129.13,129.00,126.88,126.05,122.67,122.40,117.05,112.14,53.12,37.18,6.57.

[0072] Example 6

[0073] Synthesis of compound f6

[0074]

[0075] The method is the same as in Example 1, except that the R group is replaced with 4-hydroxymethylpiperidinyl, yielding a yellow solid with a yield of 70%. 1 H NMR(500MHz,DMSO-d6)δ10.06(s,1H),8.37(d,J=8.7Hz,1H),8.32–8.27(m,1H),8.24(d,J=2.3Hz ,1H),7.98(dd,J=8.7,2.3Hz,1H),7.95–7.91(m,2H),7.73(ddd,J=8.2,5.0,3.4Hz,1H),4.47(t, J=5.3Hz,1H),3.27(t,J=5.7Hz,2H),3.13(s,2H),2.88(dt,J=11.6,3.4Hz,2H),2.12(td,J=11.4 ,2.4Hz,2H),1.65(dd,J=12.7,3.2Hz,2H),1.40–1.32(m,1H),1.27(qd,J=15.7,13.8,3.8Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ182.88,169.77,157.85,146.87,145.78,141.83,137.87,135.52,130.3 7,130.32,128.49,127.31,123.79,122.97,117.82,115.51,66.42,62.77,53.79,38.40,29.03.

[0076] Example 7

[0077] Synthesis of compound g1

[0078]

[0079] Compound e (354 mg, 1 mM) was dissolved in 30 mL of acetonitrile, followed by the addition of dimethylamine (54 mg, 1.2 mM) (R group being dimethylamino) and triethylamine (101 mg, 1.2 mM), and refluxed at 75 °C for 8–12 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed. Compound f1 was purified by column chromatography using dichloromethane:methanol (50:1) to give a yellow solid in 76% yield. 1 H NMR (500MHz, DMSO-d6) δ10.33(t,J=2.9Hz,1H),8.28(dd,J=8.8,2.1Hz,1H),8.23(d,J=7.8Hz,1H),8.13(d,J=2.2Hz,1H),7.89(d, J=4.0Hz,2H),7.79(dd,J=8.6,2.9Hz,1H),7.68(dt,J=8.2,4.2Hz,1H),2.57(t,J=7.0Hz,2H),2.46(t,J=7.0Hz,2H),2.19(s,6H). 13 C NMR(126MHz,DMSO-d6)δ182.73,171.12,157.66,146.77,145.58,141.39,138.49,135.43 ,130.34,130.26,127.64,127.23,123.69,122.85,117.87,114.65,55.38,45.40,35.21.

[0080] Example 8

[0081] Synthesis of compound g2

[0082]

[0083] The method is the same as in Example 7, except that the R group is replaced with a diethylamino group, yielding a yellow solid with a yield of 73%. 1 HNMR (500MHz, DMSO-d6) δ10.43(s,1H),8.27(d,J=8.7Hz,1H),8.21(d,J=7.8Hz,1H),8.13(d,J=2.3Hz,1H),7.89(d,J=4.0Hz,2H),7.76(dd ,J=8.7,2.3Hz,1H),7.67(dt,J=8.1,4.2Hz,1H),2.75(t,J=7.0Hz,2H),2.50(q,J=7.1Hz,4H),2.42(t,J=7.0Hz,2H),0.98(t,J=7.1Hz,6H). 13C NMR (126MHz, DMSO-d6) δ182.74,171.39,157.65,146.77,145.57,141.36,138.51,135.41,13 0.33,130.24,127.59,127.23,123.69,122.85,117.89,114.60,48.67,46.59,34.67,12.30.

[0084] Example 9

[0085] Synthesis of compound g3

[0086]

[0087] The method is the same as in Example 7, except that the R group is replaced with a morpholino group, yielding a yellow solid with a yield of 71%. 1 HNMR (500MHz, DMSO-d6) δ10.37(s,1H),8.30(d,J=8.6Hz,1H),8.24(d,J=7.8Hz,1H),8.15(d,J=2.2Hz,1H),7.90(d,J=3.8Hz,2H),7. 79(dd,J=8.7,2.3Hz,1H),7.71–7.67(m,1H),3.58(t,J=4.6Hz,4H),2.64(t,J=7.1Hz,2H),2.52–2.49(m,2H),2.42(d,J=4.7Hz,4H). 13 C NMR(126MHz,DMSO-d6)δ182.78,171.04,157.70,146.80,145.64,141.48,138.44,135.45,13 0.35,130.28,127.72,127.26,123.72,122.90,117.93,114.70,66.67,54.48,53.50,34.39.

[0088] Example 10

[0089] Synthesis of compound g4

[0090]

[0091] The method is the same as in Example 7, except that the R group is replaced with 1-methylpiperazinyl, yielding a yellow solid with a yield of 70%. 1H NMR (500MHz, DMSO-d6) δ10.42(s,1H),8.27(d,J=8.7Hz,1H),8.22(dd,J=7.8,1.2Hz,1H),8.13(d,J=2.3Hz,1H),7.89(d,J=3.9Hz,2H),7.77(dd,J= 8.7,2.3Hz,1H),7.68(dt,J=8.2,4.2Hz,1H),2.63(t,J=7.1Hz,2H),2.54 –2.48(m,2H),2.47(d,J=7.2Hz,4H),2.32(d,J=27.0Hz,4H),2.16(s,3H). 13 C NMR (126MHz, DMSO-d6) δ182.72,171.08,157.65,146.77,145.57,141.39,138.47,135.43,130.3 4,130.26,127.63,127.24,123.69,122.85,117.89,114.63,55.14,54.00,52.72,46.08,34.59.

[0092] Example 11

[0093] Synthesis of compound g5

[0094]

[0095] The method is the same as in Example 7, except that the R group is replaced with a cyclopropylamino group, yielding a yellow solid with a yield of 68%. 1 HNMR (600MHz, DMSO-d6) δ10.77(s,1H),8.39(d,J=4.3Hz,1H),8.30(d,J=3.9Hz,1H),8.24(d,J=1.1Hz,1H),7.94(d,J=1.6Hz,3H),7.73(ddd,J=4.1, 2.7,1.5Hz,1H),3.70(d,J=1.1Hz,1H),2.91(t,J=3.1Hz,2H),2.69(d,J=1 .1Hz,1H),2.30(t,J=3.1Hz,2H),0.83–0.73(m,2H),0.46(t,J=3.1Hz,2H). 13C NMR(151MHz,DMSO-d6)δ182.78,168.95,157.77,146.83,145.68,141.71,138.14,135.49,13 0.37,130.30,127.84,127.29,123.74,123.00,118.02,114.81,41.50,41.08,35.17,11.82.

[0096] Example 12

[0097] Synthesis of compound g6

[0098]

[0099] The method is the same as in Example 7, except that the R group is replaced with 4-hydroxymethylpiperidinyl, yielding a yellow solid with a yield of 73%. 1 H NMR (500MHz, DMSO-d6) δ10.47(s,1H),8.34(d,J=8.6Hz,1H),8.27(d,J=7.8Hz,1H),8.16(d,J=2.2Hz, 1H),7.92(d,J=4.0Hz,2H),7.80(dd,J=8.7,2.2Hz,1H),7.70(td,J=6.7,5.4,3.5Hz,1H),4.40(s,1H) ,3.24(t,J=5.3Hz,2H),2.96–2.84(m,2H),2.63(t,J=7.0Hz,2H),2.48(d,J=7.3Hz,2H),2.00–1.83(m ,2H),1.64(dd,J=13.1,3.6Hz,2H),1.33(ddt,J=11.2,8.2,4.2Hz,1H),1.12(qd,J=12.2,3.8Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ182.84,171.32,157.77,146.84,145.71,141.52,138.47,135.48,130.37,1 30.30,127.71,127.30,123.76,122.98,118.00,114.71,66.39,54.46,53.36,38.85,34.76,29.29.

[0100] Example 13

[0101] Synthesis of compound m1

[0102]

[0103] Compound k (339 mg, 1 mM) was dissolved in 30 mL of acetonitrile, followed by the addition of dimethylamine (54 mg, 1.2 mM) (R group being dimethylamino) and triethylamine (101 mg, 1.2 mM), and refluxed at 75 °C for 8–12 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed. Compound f1 was purified by column chromatography using dichloromethane:methanol (50:1) to give a yellow solid in 73% yield. 1 H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.71(d,J=2.4Hz,1H),8.46–8.41(m,1H),8.10(dd,J =8.8,2.5Hz,1H),7.86–7.80(m,3H),7.45(td,J=7.5,0.9Hz,1H),3.15(s,2H),2.31(s,6H). 13 C NMR (126MHz, DMSO-d6) δ182.69,169.95,157.90,146.24,144.12,142.33,140.69,138 .08,131.10,127.29,126.70,125.06,124.32,122.79,117.51,116.31,63.70,45.80.

[0104] Example 14

[0105] Synthesis of compound m2

[0106]

[0107] The method is the same as in Example 13, except that the R group is replaced with a dimethylamino group, yielding a yellow solid with a yield of 76%. 1 HNMR(500MHz,DMSO-d6)δ10.32(s,1H),8.71(d,J=2.4Hz,1H),8.46–8.41(m,1H),8.10(dd,J =8.8,2.5Hz,1H),7.86–7.80(m,3H),7.45(td,J=7.5,0.9Hz,1H),3.15(s,2H),2.31(s,6H). 13 C NMR (126MHz, DMSO-d6) δ182.69,169.95,157.90,146.24,144.12,142.33,140.69,138 .08,131.10,127.29,126.70,125.06,124.32,122.79,117.51,116.31,63.70,45.80.

[0108] Example 15

[0109] Synthesis of compound m3

[0110]

[0111] The method is the same as in Example 13, except that the R group is replaced with a morpholino group, yielding a yellow solid with a yield of 73%. 1 HNMR(500MHz,DMSO-d6)δ10.33(s,1H),8.69(d,J=2.5Hz,1H),8.49–8.43(m,1H),8.11(dd,J=8.8,2.5Hz ,1H),7.90–7.82(m,3H),7.46(td,J=7.6,0.9Hz,1H),3.69–3.63(m,4H),3.21(s,2H),2.60–2.52(m,4H). 13 C NMR (126MHz, DMSO-d6) δ182.75,169.42,157.94,146.27,144.23,142.42,140.55,138.11 ,131.16,127.32,126.73,125.10,124.36,122.83,117.53,116.35,66.53,62.54,53.62.

[0112] Example 16

[0113] Synthesis of compound m4

[0114]

[0115] The method is the same as in Example 13, except that the R group is replaced with 1-methylpiperazinyl, yielding a yellow solid with a yield of 75%. 1 H NMR (500MHz, DMSO-d6) δ10.28(s,1H),8.68(d,J=2.5Hz,1H),8.46(d,J=8.0Hz,1H),8.09(dd,J=8.8,2.5Hz ,1H),7.90–7.83(m,3H),7.46(t,J=7.5Hz,1H),3.19(s,2H),2.55(s,4H),2.48–2.30(m,4H),2.18(s,3H). 13C NMR (126MHz, DMSO-d6) δ182.73,169.59,157.92,146.25,144.19,142.37,140.56,138.10,13 1.16,127.32,126.66,125.09,124.35,122.81,117.52,116.25,62.31,54.96,53.15,46.24.

[0116] Example 17

[0117] Synthesis of compound m5

[0118]

[0119] The method is the same as in Example 13, except that the R group is replaced with a cyclopropylamine group, yielding a yellow solid with a yield of 69%. 1 HNMR(600MHz,DMSO-d6)δ10.29(s,1H),8.72–8.60(m,1H),8.44(d,J=4.1Hz ,1H),8.08(dd,J=4.4,1.3Hz,1H),7.75(d,J=4.4Hz,1H),7.69(d,J=3.8Hz,1 H),7.59(t,J=3.9Hz,1H),7.36(t,J=3.8Hz,1H),4.56–4.23(m,1H),3.42(s ,2H),2.21(dq,J=3.6,1.8Hz,1H),0.46–0.34(m,2H),0.33(t,J=1.5Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ171.66,158.46,151.15,143.69,142.49,140.44,139.62,132.3 9,129.92,126.84,126.34,125.76,122.95,121.61,116.80,115.57,53.25,37.01,6.59.

[0120] Example 18

[0121] Synthesis of compound m6

[0122]

[0123] The method is the same as in Example 13, except that the R group is replaced with 4-hydroxymethylpiperidinyl, yielding a yellow solid with a yield of 76%. 1H NMR(500MHz,DMSO-d6)δ10.25(s,1H),8.68(d,J=2.5Hz,1H),8.48–8.42(m,1H),8.10 (dd,J=8.8,2.5Hz,1H),7.89–7.81(m,3H),7.46(td,J=7.5,0.9Hz,1H),4.46(t,J=5.3 Hz,1H),3.28(t,J=5.5Hz,2H),3.18(s,2H),2.91(dt,J=11.6,3.3Hz,2H),2.20–2.08( m,2H),1.66(dd,J=12.7,3.2Hz,2H),1.39–1.33(m,1H),1.28(qd,J=11.9,3.7Hz,2H). 13 CNMR(126MHz,DMSO-d6)δ182.71,169.91,157.91,146.23,144.16,142.36,140.57,138.09,131. 14,127.30,126.69,125.08,124.33,122.80,117.51,116.28,66.41,62.83,53.76,38.40,29.05.

[0124] Example 19

[0125] Synthesis of compound n1

[0126]

[0127] Compound i (354 mg, 1 mM) was dissolved in 30 mL of acetonitrile, followed by the addition of dimethylamine (54 mg, 1.2 mM) (R group being dimethylamino) and triethylamine (101 mg, 1.2 mM), and refluxed at 75 °C for 8–12 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed. Compound f1 was purified by column chromatography using dichloromethane:methanol (50:1) to give a yellow solid in 71% yield. 1 H NMR (500MHz, DMSO-d6) δ10.56(s,1H),8.59(d,J=2.5Hz,1H),8.43(dt,J=7.6,1.0Hz,1H),7.99(dd,J=8.8,2.5Hz, 1H),7.85–7.81(m,3H),7.44(td,J=7.5,0.9Hz,1H),2.60(dd,J=7.3,6.0Hz,2H),2.51–2.49(m,2H),2.19(s,6H). 13C NMR (126MHz, DMSO-d6) δ182.66,171.37,157.86,146.20,144.00,142.08,141.12,138.06 ,131.26,127.29,126.10,125.05,124.38,122.78,117.50,115.67,55.36,45.39,35.33.

[0128] Example 20

[0129] Synthesis of compound n2

[0130]

[0131] The method is the same as in Example 19, except that the R group is replaced with a diethylamino group, yielding a yellow solid with a yield of 72%. 1 HNMR(500MHz,DMSO-d6)δ10.63(s,1H),8.59(d,J=2.4Hz,1H),8.46–8.41(m,1H),7.99(dd,J=8.8,2.5Hz,1H),7.83(td,J=8.1, 7.4,5.9Hz,3H),7.45(t,J=7.5Hz,1H),2.78(t,J=7.0Hz,2H),2.57–2.50(m,4H),2.48(d,J=6.9Hz,2H),0.99(t,J=7.1Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ182.68,171.65,157.87,146.21,143.99,142.06,141.15,138.07,13 1.29,127.29,126.07,125.05,124.42,122.79,117.50,115.63,48.68,46.61,34.83,12.28.

[0132] Example 21

[0133] Synthesis of compound n3

[0134]

[0135] The method is the same as in Example 19, except that the R group is replaced with a morpholino group, yielding a yellow solid with a yield of 74%. 1HNMR(500MHz,DMSO-d6)δ10.55(s,1H),8.59(d,J=2.5Hz,1H),8.43(d,J=8.0Hz,1H),7.99(dd,J=8.8,2.5Hz,1H),7.88–7.7 8(m,3H),7.44(t,J=7.5Hz,1H),3.58(t,J=4.6Hz,4H),2.67(t,J=7.1Hz,2H),2.55(t,J=7.0Hz,2H),2.43(t,J=4.6Hz,4H). 13 C NMR(126MHz,DMSO-d6)δ182.68,171.27,157.87,146.21,144.03,142.11,141.08,138.08,13 1.29,127.30,126.12,125.06,124.40,122.79,117.51,115.68,66.66,54.44,53.51,34.50.

[0136] Example 22

[0137] Synthesis of compound n4

[0138]

[0139] The method is the same as in Example 19, except that the R group is replaced with 1-methylpiperazinyl, yielding a yellow solid with a yield of 76%. 1 H NMR (500MHz, DMSO-d6) δ10.63(s,1H),8.64(d,J=2.5Hz,1H),8.47(d,J=8.0Hz,1H),8.01(dd,J=8.8,2.5Hz,1H),7.90–7 .83(m,3H),7.47(t,J=7.5Hz,1H),2.66(t,J=7.0Hz,2H),2.54(t,J=7.0Hz,2H),2.44(s,4H),2.33(s,4H),2.15(s,3H). 13 C NMR (126MHz, DMSO-d6) δ182.77,171.42,157.96,146.29,144.14,142.18,141.09,138.10,131.3 4,127.32,126.17,125.09,124.48,122.86,117.54,115.71,55.21,54.02,52.82,46.17,34.77.

[0140] Example 23

[0141] Synthesis of compound n5

[0142]

[0143] The method is the same as in Example 19, except that the R group is replaced with a cyclopropylamine group, yielding a yellow solid with a yield of 65%. 1 HNMR(500MHz,DMSO-d6)δ10.86(s,1H),8.69(d,J=1.6Hz,1H),8.45(d,J=4.8Hz ,1H),8.06(dd,J=5.2,1.5Hz,1H),7.80(d,J=5.3Hz,1H),7.72(d,J=4.6Hz,1H), 7.61(t,J=4.6Hz,1H),7.38(t,J=4.5Hz,1H),3.89–3.74(m,1H),2.93(s,2H),2 .74(d,J=2.2Hz,1H),2.26(d,J=2.2Hz,2H),0.90(s,2H),0.77(d,J=4.2Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ168.60,158.48,150.71,143.35,142.14,139.99,139.21,131.95,12 9.51,126.43,125.81,125.30,122.51,121.18,116.34,115.13,43.44,43.25,36.55,13.21.

[0144] Example 24

[0145] Synthesis of compound n6

[0146]

[0147] The method is the same as in Example 19, except that the R group is replaced with 4-hydroxymethylpiperidinyl, yielding a yellow solid with a yield of 74%. 1H NMR(500MHz,DMSO-d6)δ10.66(s,1H),8.58(d,J=2.5Hz,1H),8.48–8.38(m,1H),7.97(dd,J=8 .8,2.5Hz,1H),7.87–7.76(m,3H),7.44(t,J=7.5Hz,1H),4.41(s,1H),3.28–3.19(m,2H),2.9 1(dt,J=11.8,3.3Hz,2H),2.64(t,J=7.0Hz,2H),2.53(d,J=6.9Hz,2H),1.94(td,J=11.6,2.5 Hz,2H),1.71–1.60(m,2H),1.34(ddt,J=11.4,8.8,3.9Hz,1H),1.12(qd,J=12.1,3.9Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ182.67,171.51,157.85,146.20,144.00,142.07,141.11,138.07,131.30,1 27.29,126.06,125.05,124.41,122.78,117.50,115.62,66.41,54.41,53.35,38.84,34.84,29.30.

[0148] Example 25

[0149] The inhibitory effects of the compounds on acetylcholinesterase and butyrylcholinesterase were tested using Ellman's method (Biochemical Pharmacology 1961, 7, 88-95). The results were analyzed using IC50. 50 Values ​​are expressed as positive controls, with Donepezi L and Tacrine used as positive controls. All tests were performed on a PowerWave XS2 full-wavelength microplate reader at 37°C. Data analysis was performed using Origin software.

[0150] Experimental steps:

[0151] (1) Preparation of drug solution:

[0152] Weigh a certain amount of each sample to be analyzed and dissolve it in dimethyl sulfoxide (DMSO) to prepare a 10 mM concentration. Store it in a -20°C freezer. Before use, dilute it with phosphate buffer (0.1 mol / L, pH=8.0) to the required concentration so that the final concentration of DMSO is less than or equal to 0.5% (v / v).

[0153] (2) Preparation of enzyme stock solution:

[0154] Acetylcholinesterase (EC3.1.1.7, from electric ell.) and butyrylcholinesterase (EC3.1.1.8, from equine serum) were purchased from Sigma. Weigh out a certain amount of acetylcholinesterase or butyrylcholinesterase and dilute it with deionized water to the appropriate activity range.

[0155] (3) Preparation of substrate stock solution:

[0156] Acetylthiocholine (ATC) and butylthiocholine (BTC) were purchased from Sigma-Aldrich. A certain amount of ATC or BTC was weighed and prepared into a 0.01 mol / L solution with phosphate buffer (0.1 mol / L, pH 8.0), and stored at 4°C in the dark.

[0157] (4) Preparation of the colorimetric reagent stock solution:

[0158] The colorimetric reagent 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) was purchased from Sigma-Aldrich. A certain amount of DTNB was weighed and prepared into a 0.01 mol / L solution with phosphate buffer (0.1 mol / L, pH 8.0), and stored at 4°C in the dark.

[0159] (5) Enzyme inhibition test

[0160] The compound dissolved in DMSO was diluted to different concentrations with PB (phosphate buffer) solution, and then added to 48-well plates (100 μL per well). The plates were then incubated with 100 μL of AChE or BuChE at 37°C for 20 minutes. After 20 minutes, 100 μL of substrate (iodothioacetylcholine or S-iodide butyrylthiocholine) and 100 μL of PB solution were added to the 48-well plates. Then, 100 μL of chromogenic material (5,5-dithiobis-(2-nitrobenzoic acid, DTNB, Ellman's reagent) was added and incubated for 5 minutes. The absorbance was then measured at 419 nm using a multi-microplate reader.

[0161] (6) Calculation of results:

[0162] IC 50 Value calculation: The change in absorbance (slope) measured without the addition of inhibitor is taken as 100 activity units (Acontrol). Relative enzyme activity = (absorbance change with inhibitor / absorbance change without inhibitor) × 100. When the relative enzyme activity reaches 50, it is the IC50 of the inhibitor. 50 value.

[0163] The experimental results are the average of three independent experiments.

[0164] (7) Experimental results:

[0165] Table 1. Inhibitory activities of compounds against acetylcholinesterase and butyrylcholinesterase

[0166]

[0167]

[0168] a Selectivity for acetylcholinesterase = IC 50 (Butyrylcholinesterase) / IC 50 (acetylcholinesterase)

[0169] (8) Results and Discussion: Table 1 shows that the synthesized compounds all exhibited good inhibitory activity against acetylcholinesterase, with activities ranging from 12.17 to 1235.46 nM, while their inhibitory activity against butyrylcholinesterase was weaker. The selectivity for acetylcholinesterase was high, ranging from 6.4 to 517.1. This suggests that compounds f1-n6 have the potential to be developed into acetylcholinesterase inhibitors and further into AD treatment drugs. Among the above compounds, n1 exhibited the best acetylcholinesterase inhibitory activity (IC50). 50 It has a concentration of 12.17 ± 1.50 nM and the best acetylcholinesterase inhibitory selectivity (517.1), making it a potential drug for the treatment of AD.

[0170] Example 26

[0171] ThT fluorescence method for studying the inhibition of Aβ aggregation by compounds

[0172] The accumulation of Aβ peptides in the brain promotes the formation of senile plaques and reactive oxygen species (ROS), and is considered one of the main pathogenesis mechanisms of Alzheimer's disease (AD). This study investigated the inhibitory effect of tested compounds on Aβ aggregation using thiosulfate T (ThT) fluorescence analysis. 1-42 The sample was dissolved in phosphate buffer (pH 7.4) containing 1% ammonium hydroxide. The test compound was prepared in DMSO to obtain a 10 mM solution, which was then further diluted with phosphate buffer.

[0173] Specific method: In the presence of 100 μL of the test compound, react with 10 μL of Aβ. 1-42 When incubated together, the resulting mixture contains Aβ 1-42The final concentration was 20 μM, and the final concentration of the test compound was 100 μM. The mixture was incubated in the dark at 37°C for 48 hours, then 5 μM ThT (prepared in 50 mM glycine-NaOH buffer; pH 8.5) was added to a volume of 200 μL. The fluorescence intensity of the solution was measured using a PerkinElmer EnSpire microplate reader at an excitation wavelength of 450 nm and an emission wavelength of 485 nm. The effect of the test compound on Aβ was calculated using the following formula. 1-42 The percentage of aggregation inhibition is calculated as (1-IFi / IFo)×100%, where IFi represents the fluorescence intensity when the test compound is added, and IFo represents the fluorescence intensity of the control group.

[0174] Table 2. Effects of compounds on Aβ aggregation

[0175]

[0176] a The inhibitory effect of Aβ self-aggregation was determined by ThT fluorescence analysis in the presence of 5 μM Aβ and 100 μM inhibitor. Data are presented as mean ± SEM of three independent experiments, each of which was performed in duplicate.

[0177] Results Analysis: As shown in Table 2, compound n1 significantly inhibited Aβ compared with the positive control drugs donepezil (100 μM) and curcumin (20 μM). 1-42 The inhibition rate of protein self-aggregation was 63.48±1.02%.

[0178] Example 27

[0179] TEM method for observing changes in the inhibitory effect of compounds on Aβ aggregation

[0180] Transmission electron microscopy (TEM) is a high-resolution, high-magnification microscope used to observe the submicroscopic structure of samples such as tissues, cells, and proteins. In this study, TEM images were taken at different time points to investigate the effect of the test compound on Aβ. 1-42 Protein morphological changes due to aggregation inhibition. Specifically: Samples were prepared in the same manner as described above and incubated for 48 hours. At specified time points, aliquots of 10 μL sample were placed on carbon-coated copper / rhodium grids. After 1 minute, the grids were washed with water and negatively stained with 2% uranyl acetate solution for 1 minute. After filtering off excess staining solution with filter paper, the samples were transferred to a transmission electron microscope (JEOL JEM-100SX) for examination.

[0181] The results are as follows Figure 1 As shown in the figure, (A)Aβ 1-42 Incubate alone for 0 hours; (B)Aβ 1-42Incubate alone for 48 hours; (C)Aβ 1-42 Incubate with compound n1 (100 μM) for 48 hours; (D)Aβ 1-42 Incubate with donepezil (100 μM) for 48 hours; (E)Aβ 1-42 Incubate with curcumin (20 μM) for 48 hours.

[0182] like Figure 1 As shown, with Aβ incubated for 0h 1-42 In contrast, after 48 hours of incubation, significant self-aggregation was observed. However, when Aβ... 1-42 When incubated with compound n1 for 48 hours, Aβ 1-42 Protein aggregation was significantly inhibited, which further demonstrates that compound n1 inhibits Aβ self-aggregation.

[0183] Example 28

[0184] The mouse neuronal cell line PC12, which inhibits H2O2-induced cytotoxicity, was routinely cultured in DMEM complete medium containing 10% fetal bovine serum at 37°C in a humidified incubator with 5% CO2 and 95% air. Cells in the logarithmic growth phase were harvested, digested with 0.25% trypsin solution, and resuspended in complete medium. Cells were counted under a microscope using a cell counting chamber, and the cell concentration was adjusted to 1 × 10⁻⁶ cells / mL. 5 Cells were seeded at 100 μL / well in 96-well cell culture plates and cultured overnight to allow cell adhesion. The experiment included a test sample group, a blank group, and a solvent control group. The culture medium in the 96-well cell culture plates was discarded, and the test sample group solution was added. The blank group received complete culture medium without the compound, and the solvent control group received the same concentration of DMSO. After pre-incubation for 30 min, 150 μM hydrogen peroxide was added. The model group did not receive the test compound; 140 μM hydrogen peroxide was added directly. After incubation for 24 h, the cells were protected from light, and 20 μL of 5 mg / mL MTT stock solution was added to each well, and the cells were cultured for 4 h. The culture medium in the 96-well cell culture plates was discarded, and 100 μL of DMSO was added to each well. The plates were shaken to completely dissolve the formazan in the DMSO, and the absorbance of each well was measured at 570 nm using a microplate reader. Cell survival rate was calculated using the formula: Compound promotes cell survival rate (%) = 100% * (A test compound - A model group) / (A model group - A blank).

[0185] Figure 2 To detect the protective effects of compound n1 and quercetin against H2O2-induced PC12 cell damage using the MTT assay. Values ​​from three independent experiments are expressed as mean ± standard deviation. Results are presented as mean ± SD (n = 3) from at least three independent experiments. ##p<0.01 compared with the control group, **p<0.01, *p<0.05 compared with H2O2-induced cells.

[0186] from Figure 2 It can be seen that compound n1 increased the survival rate of H2O2-induced PC12 cells, with compound n1 exhibiting the best inhibitory activity. At 10 μM, compound n1 increased the survival rate of H2O2-induced PC12 cells to 60.37 ± 0.3%, which was significantly better than the positive control drug quercetin. This suggests that this class of compounds has a neuroprotective effect to some extent.

[0187] Example 28

[0188] Morris water maze experiment

[0189] 1) Male C57BL mice (18-23g), 8 weeks old, were purchased from the Experimental Center of Anhui University of Traditional Chinese Medicine. The mice were housed under standard conditions in a temperature and humidity controlled environment (23℃~25℃, 40%~60%, 12h).

[0190] 2) Treatment and modeling:

[0191] Thirty mice were randomly divided into five groups. The normal control group and the model group were administered 0.5% sodium carboxymethyl cellulose (CMC-Na) solution by gavage for 7 days. The drug group and the positive control group were administered different concentrations of n1 (20 mg / kg, 10 mg / kg) and donepezil (10 mg / kg) by gavage, respectively. On day 7, except for the normal control group (physiological saline), the mice in the other groups were injected with scopolamine to establish the AD model.

[0192] 3) Morris Water Maze Test

[0193] The MWM device mainly consists of a circular water tank (150 cm in diameter and 60 cm in height), a 10 cm diameter escape platform, a data acquisition system, and an analysis system. First, the circular water tank was filled with water (1.0 cm above the escape platform), and titanium dioxide (0.25 g / L) was added to make the water turbid. The platform was fixed in the third quadrant of the circular water tank (out of four quadrants). All mice were trained for four days, with four training trials per day.

[0194] A mouse (head facing the pool wall) was randomly placed in one of the four quadrants. If the mouse successfully found the platform within 60 seconds, it was allowed to stay on the platform for 15 seconds; otherwise, it was taken to the platform and allowed to stay there for 15 seconds. Four days later, the platform was removed from its position, and the mouse was placed in the first quadrant, the furthest from the platform, to search for the platform (60 seconds). The time spent in the platform quadrant and the number of times the mouse entered that area within 60 seconds were recorded.

[0195] The results are as follows Figure 3-8 As shown. From Figure 3 It can be seen that different concentrations of compound n1 did not cause abnormal fluctuations or significant adverse effects on the body weight of mice during the 7-day administration period. Figure 4 It can be seen that there was no significant difference in swimming speed between the drug group and the normal group. Furthermore, compared to the model group, the swimming speed... Figure 5 It can be seen that the drug group reduced the time for mice to find the platform in a dose-dependent manner, i.e., reduced the escape latency of the mice. On the fifth day, by Figure 6 and Figure 7 It can be seen that when the platform was removed, mice treated with a dose of 20 mg / kg had significantly better time spent in the target quadrant and more crossovers on the virtual platform via the space probe experiment than mice treated with a dose of 10 mg / kg. Figure 8 The figure shows the representative trajectory of mice in the Morris water maze test. As can be seen from the figure, after the platform was removed, except for the normal group, the mice treated with a dose of 20 mg / kg took significantly less time to enter the platform quadrant and entered the area more frequently than the other groups.

[0196] Experiments show that the compound n1 involved in this invention can significantly improve the learning and memory abilities and behaviors of AD animal models in terms of space and orientation, and its effect is superior to donepezil, a first-line clinical drug, indicating that compound n1 has the potential to be developed into an effective treatment for Alzheimer's disease.

[0197] The above are merely preferred embodiments of the present invention and are not intended to limit the scope of the invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An amide-substituted tryptophanone derivative, characterized by, The structural formulas of the tryptophan ketone derivatives are shown in formula (A) or formula (B): （A） （B） In the formula, n = 1 or 2; when n = 1, R is a dimethylamino group; when n = 2, R is either a dimethylamino group or a diethylamino group.

2. A process for the preparation of an amide-substituted tryptophanone derivative according to claim 1, characterized in that, The method for preparing tryptophan ketone derivatives with the structure shown in formula (A) includes the following steps: S1. Under nitrogen protection, indomethacin anhydride reacts with indomethacin in triethylamine and toluene to yield tryptamine ketone; S2. Nitrate tryptophanone under HNO3 conditions to obtain 8-nitrotryptophanone; S3. 8-Nitrotryptamine ketone is reduced by SnCl2 and HCl to give 8-aminotryptamine ketone; S4. 8-Aminotryptamine ketone reacts with chloroacetyl chloride or chloropropionyl chloride to give the corresponding acylated products; S5. The acylated products prepared in step S4 are reacted with amines having the corresponding R groups in acetonitrile solution. The purified products are amide-substituted tryptamine ketone derivatives having the structure shown in formula (A); the R group is either dimethylamino or diethylamino. The method for preparing tryptophan ketone derivatives with the structure shown in formula (B) includes the following steps: S1. Indomethacin anhydride yields the precursor of the compound in concentrated H2SO4 in the presence of KNO3; S2. The precursor compound reacts with indigo under the protection of triethylamine and nitrogen to undergo a dehydration condensation reaction, yielding 2-nitrotryptamine ketone; S3.2-nitrotryptamine and stannous chloride dihydrate were added to an ethanol-hydrochloric acid solution and then hydrogenated to reduce the 2-aminotryptamine. S4. 2-Aminotryptamine ketone reacts with chloroacetyl chloride or chloropropionyl chloride to give the corresponding acylated products; S5. The acylated products prepared in step S4 are reacted with amines having the corresponding R groups in acetonitrile solution. After purification, the products are amide-substituted tryptamine ketone derivatives having the structure shown in formula (B); the R group is either dimethylamino or diethylamino.

3. The production method according to claim 2, wherein In step S5, the solvent for the reaction is acetonitrile, the reaction temperature is 75℃, and the stirring time is 4-6 hours.

4. The use of an amide-substituted tryptamine derivative as described in claim 1 in the preparation of an acetylcholinesterase inhibitor.

5. The use of an amide-substituted tryptamine derivative as described in claim 1 in the preparation of a medicament for treating Alzheimer's disease.

6. An acetylcholinesterase inhibitor comprising a pharmaceutically effective dose of the tryptophan derivative as described in claim 1.

7. A medicament for treating Alzheimer's disease, comprising a pharmaceutically effective dose of the tryptophan derivative as described in claim 1.

8. The medicament according to claim 6 or 7, characterized in that The drug also contains a pharmaceutically acceptable carrier.

9. The medicament according to claim 8, wherein The pharmaceutically acceptable carriers include carriers that function as one or more of the following: excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents.

10. The medicament according to claim 9, wherein The drug is any one of the following: injection, tablet, pill, capsule, suspension, or emulsion.

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