A class of quinoline derivatives containing hydroxamic acid fragments and their preparation method and application

Abstract

The present invention belongs to the field of medicinal chemistry and discloses quinoline derivatives containing a hydroxamic acid fragment as shown in Formula I. Wherein, R1 is selected from H, 7-Cl, 2-Me, 2-Ph; R2 is selected from ‑(CH2)2-, ‑(CH2)3-, ‑(CH2)6-, ‑C6H4-; and R3 is selected from ‑(CH2)2-, ‑(CH2)3-, ‑(CH2)4-, ‑(CH2)6-, ‑C6H4-. The synthetic raw materials of the quinoline derivatives containing a hydroxamic acid fragment of the present invention are readily available, the preparation method is simple, and the operation is easy. The quinoline derivatives containing a hydroxamic acid fragment have good cholinesterase inhibitory activity, and some of the compounds have stronger activity than the clinical drug rivastigmine, and are expected to be developed into new cholinesterase inhibitors for Alzheimer's disease.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a quinoline derivative containing a hydroxamic acid fragment, a preparation method thereof, and an application thereof in the preparation of an anti-Alzheimer's disease drug. Background Art

[0002] Alzheimer's disease is a common neurodegenerative disease in the elderly that progresses slowly, worsening over time and becoming irreversible. Early symptoms primarily manifest as intellectual impairment, which clinically manifests as forgetfulness, language impairment, long-term memory loss, difficulty caring for oneself, and abnormal behavior, leading to a gradual loss of bodily functions and ultimately death. The pathogenesis of Alzheimer's disease remains unclear, and the disease progresses irreversibly, placing a heavy financial and economic burden on patients and their families, making it a significant public health issue in contemporary society.

[0003] There is a very close connection between the neuropathology of Alzheimer's disease and the cholinergic hypothesis. The development of anti-Alzheimer's drugs based on this hypothesis is a very effective and widely adopted strategy. Currently, most anti-Alzheimer's drugs used in clinical practice are acetylcholinesterase inhibitors, such as donepezil, huperzine A, galantamine, and rivastigmine. However, the therapeutic effects of these drugs are limited, and they can only alleviate the disease to a certain extent. They are often accompanied by a series of serious side effects such as nausea, vomiting, insomnia, and fatigue. Therefore, there is still an urgent need to develop new, safer and more effective cholinesterase inhibitors.

[0004] Nitrogen-containing heterocycles play an extremely important role in drug research, among which quinoline is one of the most important skeletons in synthetic chemistry and medicinal chemistry. Quinoline and its derivatives are an important class of active natural products, often serving as core fragments of a variety of active molecules, exhibiting a wide range of biological activities, such as anticancer, antibacterial, antiviral, antimalarial, anti-inflammatory, and anti-Alzheimer's activities. At the same time, the hydroxamic acid fragment is considered to be an important component of many bioactive molecules and is regarded as a potential pharmacophore for anti-Alzheimer's drugs. Therefore, the present invention designs a quinoline derivative containing a hydroxamic acid fragment as an effective cholinesterase inhibitor, which has great prospects for development as a new anti-Alzheimer's drug. Summary of the Invention

[0005] Based on the above research background, the present invention introduces a hydroxamic acid fragment at the C-4 position of the quinoline parent nucleus to increase hydrogen bond donors and acceptors, providing a class of quinoline derivatives containing hydroxamic acid fragments, their preparation method, and their application in treating Alzheimer's disease.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A quinoline derivative containing a hydroxamic acid fragment as shown in formula I,

[0008]

[0009] Wherein, R1 is selected from H, 7-Cl, 2-Me, 2-Ph; R2 is any one of the following: -(CH2)2-, -(CH2)3-, -(CH2)6-, -C6H4-; R3 is any one of the following: -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, -C6H4-.

[0010] Another object of the present invention is to provide a method for preparing a quinoline derivative containing a hydroxamic acid fragment as shown in Formula I. The synthetic route of the derivative is as follows:

[0011]

[0012] The specific synthesis steps are as follows:

[0013] Step (a): Compound 1 is added to a DMF solution of dicarboxylic acid monomethyl ester, triethylamine, and an acid amine condensing agent, benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), and stirred at 70°C for 4 hours. After the reaction is complete, the reaction solution is poured into saturated brine. If a large amount of precipitate is formed, the precipitate is collected, the filter cake is washed with water, and dried. Otherwise, the reaction solution is extracted with ethyl acetate, and the combined organic layers are washed three times with saturated brine, dried over anhydrous Na2SO4, and the organic solvent is removed under reduced pressure. The crude product is recrystallized from DMF-MeOH to obtain intermediates 2a-2t.

[0014] Step (b): A methanol solution of KOH was added dropwise to a methanol solution of hydroxylamine hydrochloride, and stirred at 0°C for 30 minutes. The precipitate was filtered off to obtain a methanol solution of hydroxylamine. Then, compound 2 was added to the freshly prepared methanol solution of hydroxylamine and stirred at 45°C for 4 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure, the residue was poured into water, and the pH was adjusted to 7 with a 2M hydrochloric acid solution. The formed precipitate was collected and recrystallized from DMF-MeOH to obtain the target compound I1-I 20 .

[0015] In step (a), the molar ratio of compound 1, monomethyl dicarboxylate, Et3N and HBTU is 1.1:1:3:1.1, and the reaction temperature is 70°C.

[0016] In step (b), the molar ratio of compound 2, hydroxylamine hydrochloride and KOH is 0.1:1:1, and the reaction temperature is 45°C.

[0017] Pharmacological experiments have shown that the quinoline derivatives containing hydroxamic acid fragments described herein exhibit good inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with some compounds exhibiting inhibitory activity stronger than that of the clinical anti-Alzheimer's disease drug rivastigmine. Therefore, another object of the present invention is to provide the use of the quinoline derivatives containing hydroxamic acid fragments in the preparation of anti-Alzheimer's disease drugs.

[0018] The anti-Alzheimer's disease drug is a drug that inhibits cholinesterase activity.

[0019] The beneficial effects of the present invention are:

[0020] The quinoline derivatives containing hydroxamic acid fragments of the present invention are made from readily available raw materials, have a simple synthesis method, and are easy to operate. Pharmacological experiments have shown that the quinoline derivatives containing hydroxamic acid fragments of the present invention have good cholinesterase inhibitory activity and stable properties, and are expected to be developed into new anti-Alzheimer's disease drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the general structural formula of the quinoline derivative containing a hydroxamic acid fragment of the present invention;

[0022] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound I6 prepared in Example 2 of the present invention;

[0023] Figure 3 is the carbon NMR spectrum of compound I6 prepared in Example 2 of the present invention;

[0024] Figure 4 Compound 1 prepared in Example 2 of the present invention 18 H NMR spectrum;

[0025] Figure 5 Compound 1 prepared in Example 2 of the present invention 18 C NMR spectrum. DETAILED DESCRIPTION

[0026] The specific embodiments of the present invention are described in detail below with reference to the examples.

[0027] Example 1: Preparation of Intermediate 2

[0028] Dissolve dicarboxylic acid monomethyl ester, Et3N, and HBTU in DMF at a molar ratio of 1:3:1.1. Mix thoroughly, then add 1.1 equivalents of compound 1. Heat to 70°C and react for 4 hours. After completion, pour the reaction mixture into saturated brine. If a large amount of precipitate forms, collect the precipitate, wash the filter cake with water, and dry it. Otherwise, extract the reaction mixture with ethyl acetate. The combined organic phases are washed three times with saturated brine, dried over anhydrous Na2SO4, and the organic solvent removed under reduced pressure. The crude product is recrystallized from DMF-MeOH to yield intermediates 2a-2t.

[0029]

[0030] Table 1 Preparation of Intermediate 2

[0031]

[0032] Example 2: Preparation of Quinoline Derivative I Containing Hydroxamic Acid Fragment

[0033] The methanol solution of KOH was added dropwise to an equimolar amount of methanol solution of hydroxylamine hydrochloride, and stirred at 0°C for 30 minutes. The precipitate was filtered off to obtain a methanol solution of hydroxylamine. Then, 0.1 equivalent of compound 2 was added to the freshly prepared methanol solution of hydroxylamine and stirred at 45°C for 4 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure, the residue was poured into water, and the pH was adjusted to 7 with a 2M hydrochloric acid solution. The formed precipitate was collected and recrystallized from DMF-MeOH to obtain the target compounds I1-I 20 .

[0034]

[0035] The structural characterization of the quinoline derivative I containing a hydroxamic acid fragment is as follows:

[0036] N 1 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 4 -Hydroxyterephthalamide (I1): white solid; yield: 76%; melting point: 221.2–221.8°C; 1 H NMR (400MHz, DMSO-d6) δ: 11.32 (s, 1H), 9.15 (s, 1H), 8.81 (s, 1H), 8.40 (d, J=5.4Hz, 1H), 8.19 (d, J= 9.1Hz,1H),7.89–7.77(m,4H),7.48–7.43(m,2H),6.62(d,J=5.4Hz,1H),3.53(s,2H),3.46(s,2H). 13CNMR(100MHz,DMSO-d6)δ:166.6(2C),152.4,150.5,149.5,137.0,135.6,1 33.9,128.0,127.7(2C),127.3(2C),124.6,124.4,117.9,99.1,42.3,40.9.

[0037] N 1 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 5 -Hydroxyglutaramide (I2): white solid; yield: 80%; melting point: 182.8–183.6°C; 1 H NMR(400MHz, DMSO-d6)δ:10.34(s,1H),8.68(s,1H),8.38(d,J=5.3Hz,1H),8.15(d,J=9.0Hz,1H ),8.05(s,1H),7.76(s,1H),7.43(d,J=9.0Hz,1H),7.38(s,1H),6.53(d,J=5.3Hz,1H),3.33(br s, 4H), 2.06 (t, J = 7.5Hz, 2H), 1.93 (t, J = 7.5Hz, 2H), 1.70 (t, J = 7.5Hz, 2H). 13 C NMR (100MHz, DMSO-d6)δ:172.8,169.2,152.3,150.5,149.5,133.9,127.9,124.6,124.3,117.8,99.0,42.7,37.7,35.2,32.2,21.8.

[0038] N 1 -(3-((7-chloroquinolin-4-yl)amino)propyl)-N 4 -Hydroxyterephthalamide (I3): white solid; yield: 75%; melting point: 212.4–213.2°C; 1 H NMR(400MHz,DMSO-d6)δ:11.35(s,1H),9.47(s,1H),8.89(s,1H),8.67(d,J =9.0Hz,1H),8.47(d,J=6.8Hz,1H),7.97(d,J=2.2Hz,1H),7.91(d,J=8.0Hz, 2H),7.78(d,J=8.0Hz,2H),7.65(dd,J=9.0,2.2Hz,1H),6.79(d,J=6.8Hz,1H ),3.55(q,J=6.5Hz,2H),3.37(q,J=6.3Hz,2H),1.92(t-like,J=6.7Hz,2H).13 C NMR(100MHz,DMSO-d6)δ:166.0(2C),155.0,144.3,140.3,137.7,137.0,135. 4,127.7(2C),127.2(2C),126.8,126.1,120.5,116.2,99.0,41.1,37.2,27.8.

[0039] N 1 -(6-((7-chloroquinolin-4-yl)amino)hexyl)-N 4 -Hydroxyterephthalamide (I4): white solid; yield: 73%; melting point: 202.8–203.4°C; 1 H NMR(400MHz, DMSO-d6)δ:8.51(s,1H),8.34(d,J=5.4Hz,1H),8.25(d,J=8.8Hz,1H),7.84(d,J=8.0Hz,2H ),7.78(d,J=8.0Hz,2H),7.74(s,1H),7.40(d,J=8.8Hz,1H),7.27(s,1H),6.42(d,J=5.4Hz,1H),3.23(br s,4H),1.64(p,J=7.3Hz,2H),1.52(p,J=7.2Hz,2H),1.41–1.34(m,4H). 13 C NMR(100MHz,DMSO-d6)δ:165.9,163.7,152.4,150.5,149.5,137.2,135.6,133.8,127.9 (2C),127.6(2C),127.1,124.6,124.4,117.9,99.0,42.8,39.6,29.5,28.2,26.8,26.7.

[0040] N 1 -Hydroxy-N 4 -(2-((2-methylquinolin-4-yl)amino)ethyl)terephthalamide (I5): white solid; yield: 72%; melting point: 220.4–221.2°C; 1H NMR (400MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.11 (d, J = 8.4Hz, 1H), 7.92 (d, J = 8.2Hz, 2H), 7.83 (d, J = 8.2Hz, 2H), 7.69 (d, J = 8.4Hz, 1H), 7.56(t,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),7.27(s,1H),6.51(s,1H),3.57(t,J=6.1Hz,2H),3.49(t,J=6.1Hz,2H),2.45(s,3H). 13 C NMR(100MHz,DMSO-d6)δ:166.6,163.7,159.0,150.5,148.2,137.0,135.6,129 .2,128.5,127.7(2C),127.3(2C),123.6,121.8,117.9,98.5,42.4,38.6,25.5.

[0041] N 1 -Hydroxy-N 4 -(3-((2-methylquinolin-4-yl)amino)propyl)terephthalamide (I6): white solid; yield: 75%; melting point: 177.8–179.2°C; 1 H NMR(400MHz, DMSO-d6)δ:9.20(s,1H),8.94(s,1H),8.58(d,J=8.5Hz,1H),7.94(d,J=8.2Hz,2H),7.89(d,J=8.4Hz,1H),7.84–7. 79(m,3H),7.55(t,J=7.7Hz,1H),6.68(s,1H),3.55(q,J=6.4Hz,2H),3.39(q,J=6.4Hz,2H),2.57(s,3H),1.93(p,J=6.9Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ:166.0,163.8,154.8,154.7,139.3,137.0,135.4,133.1, 127.7(2C),127.3(2C),126.1,123.5,120.8,116.4,98.6,40.8,37.2,27.8,20.8.

[0042] N 1 -Hydroxy-N 4 -(6-((2-methylquinolin-4-yl)amino)hexyl)terephthalamide (I7): white solid; yield: 74%; melting point: 150.2–151.4°C; 1H NMR(400MHz, DMSO-d6)δ:8.59(s,1H),8.38(d,J=9.4Hz,2H),7.96–7.70(m,6H),7.47(t,J=8.0Hz,1H),6.55(s,1H),3.36(br s,2H),3.24(br s,2H),2.54(s,3H),1.65(br s,2H),1.51(br s,2H),1.35(br s,4H). 13 C NMR(100MHz,DMSO-d6)δ:166.0,165.8,163.8,155.9,153.6,137.3,135.3,132.0,129.5,1 27.6(2C),127.2(2C),125.3,123.0,116.7,98.5,43.1,39.6,29.5,28.1,26.7(2C),22.2.

[0043] N 1 -Hydroxy-N 4 -(2-((2-phenylquinolin-4-yl)amino)ethyl)terephthalamide (I8): white solid; yield: 74%; melting point: 209.2–211.0°C; 1 H NMR(400MHz, DMSO-d6)δ:8.83(s,1H),8.24(d,J=7.5Hz,2H),8.18(d,J=8.1Hz,1H),7.85(br s,4H),7.63(t,J=7.5Hz,1H)7.52–7.43(m,5H),7.20(s,1H),3.62(br s,4H). 13 C NMR(100MHz,DMSO-d6)δ:167.1(2C),157.1,151.2,148.7,140.5,137.5,135.1,129.8,129.6, 129.3,128.8(2C),127.6(2C),127.3(2C),126.5(2C),124.3,121.8,118.5,95.5,42.5,38.6.

[0044] N 1 -Hydroxy-N 4 -(3-((2-phenylquinolin-4-yl)amino)propyl)terephthalamide (I9): white solid; yield: 80%; melting point: 174.2–175.4°C; 1H NMR(400MHz, DMSO-d6)δ:11.43(s,1H),9.18(s,1H),8.85(s,1H),8.30(d,J=8.3Hz,1H),8.16(d,J= 7.0Hz,2H),7.97(d,J=7.9Hz,2H),7.85(t-like,J=9.6Hz,3H),7.64(t,J=7.7Hz,1H),7.49–7.41(br s,5H),6.98(s,1H),3.53(q,J=6.5Hz,2H),3.45(d,J=6.1Hz,2H),1.99(br s,2H). 13 C NMR(100MHz,DMSO-d6)δ:166.1(2C),156.9,151.3,148.5,140.4,137.2,135.4,129.7,129.5,12 9.4,128.9(2C),127.7(2C),127.6(2C),127.3(2C),124.3,122.1,118.5,95.4,37.6(2C),28.2.

[0045] N 1 -Hydroxy-N 4 -(6-((2-phenylquinolin-4-yl)amino)hexyl)terephthalamide (I 10 ): white solid; yield: 72%; melting point: 202.8–203.4°C; 1 H NMR(400MHz,DMSO-d6)δ:10.32(s,1H),9.92(s,1H),8.93(s,1H),8.66(s,1H),8.3 6(d,J=8.4Hz,1H),7.95(d,J=7.4Hz,2H),7.90(d,J=8.4Hz,1H),7.70–7.65(m,3H) ,7.50–7.37(m,4H),7.34(d,J=8.4Hz,2H),7.24(s,1H),2.28(t,J=7.4Hz,2H),1.9 2(t,J=7.4Hz,2H),1.57(t,J=7.4Hz,2H),1.47(p,J=7.2Hz,2H),1.30–1.24(m,4H). 13C NMR(100MHz,DMSO-d6)δ:171.5,169.5,157.0,149.7,149.3,140.3,136.3,135.6,130.1,129.9,129.5,129 .1(2C),127.3(2C),124.9,124.3(2C),122.3,120.6(2C),119.1,98.2,36.8,32.7,28.9,28.9,25.5,25.5.

[0046] N 1 -Hydroxy-N 4 -(4-(quinolin-4-amino)phenyl)terephthalamide (I 11 ): yellow solid; yield: 60%; melting point: 227.4–228.2°C; 1 HNMR(400MHz,DMSO-d6)δ:10.44(s,1H),9.00(s,1H),8.42–8.40(m,2H),8.07–7.97(m,4H),7.85(d-like ,J=8.4Hz,3H),7.67(t,J=7.7Hz,1H),7.50(t,J=7.6Hz,1H),7.35(d,J=8.4Hz,2H),6.83(d,J=5.3Hz,1H). 13 CNMR(100MHz,DMSO-d6)δ:168.2,165.4,150.9,149.1,148.7,137.8,136.5,135.8,129 .7,129.6(2C),129.4,128.0(2C),125.0,123.8(2C),122.6,121.9(2C),120.0,101.4.

[0047] N 1 -Hydroxy-N 4 -(4-(quinolin-4-amino)phenyl)succinamide (I 12 ): yellow solid; yield: 55%; melting point: 178.6–179.8°C; 1H NMR (400MHz, DMSO-d6) δ: 10.52 (s, 1H), 10.26 (s, 1H), 8.62 (d, J = 8.4Hz, 1H), 8.44 (d, J = 5.9Hz, 1H), 7.98 (d, J = 8.4Hz, 1H), 7.84 (t, J = 7.6Hz, 1H), 7.74 (d, J = 8.3Hz, 2H), 7.63 (t, J = 7.7Hz, 1H), 7.35 (d, J = 8.3Hz, 2H), 6.75 (d, J = 5.9Hz, 1H), 2.62 (t, J = 7.4Hz, 2H), 2.33 (t, J = 7.4Hz, 2H). 13 C NMR(100MHz,DMSO-d6)δ:170.7,168.8,152.0,147.2,144.3,137.6,133.9,131.8,126.0,125.3(2C),123.3,120.4(2C),118.7,100.7,32.0,27.9.

[0048] N 1 -Hydroxy-N 6 -(4-(Quinolin-4-ylamino)phenyl)adipamide (I 13 ): yellow solid; yield: 56%; melting point: 221.1–221.8°C; 1 HNMR(400MHz,DMSO-d6)δ:10.36(s,1H),9.91(s,1H),8.85(s,1H),8.38–8.33(m,2H),7.82(d,J=8.4Hz,1H),7.66– 7.61(m,3H),7.47(t,J=7.7Hz,1H),7.25(d,J=8.3Hz,2H),6.74(d,J=5.3Hz,1H),2.28(s,2H),1.96(s,2H),1.54(br s,4H). 13 CNMR(100MHz,DMSO-d6)δ:171.4,169.4,151.1,149.3,148.7,136.2,135.6,12 9.6,124.9,124.2(2C),122.4,120.5(2C),119.9,101.2,36.6,32.6,25.3(2C).

[0049] N 1 -Hydroxy-N 8 -(4-(quinolin-4-ylamino)phenyl) suberamide (I 14 ): yellow solid; yield: 62%; melting point: 180.2–181.2°C; 1HNMR(400MHz,DMSO-d6)δ:10.36(s,1H),9.94(s,1H),8.91(s,1H),8.40(t-li ke,J=7.5Hz,2H),7.86(d,J=8.4Hz,1H),7.70–7.65(m,3H),7.51(t,J=7.6Hz,1 H),7.29(d,J=8.4Hz,2H),6.77(d,J=5.3Hz,1H),2.31(t,J=7.4Hz,2H),1.99– 1.94(m,2H),1.60(t-like,J=7.1Hz,2H),1.51(t-like,J=7.2Hz,2H),1.30(br s,4H). 13 CNMR(100MHz,DMSO-d6)δ:171.5,169.6,151.0,149.2,148.8,136.3,135.6,129.6,129.5 ,124.9,124.2(2C),122.5,120.5(2C),119.9,101.2,36.8,32.7,28.9,28.9,25.5,25.5.

[0050] N 1 -(4-((7-chloroquinolin-4-yl)amino)phenyl)-N 5 -Hydroxyglutaramide (I 15 ): yellow solid; yield: 50%; melting point: 187.4–188.6°C; 1 H NMR(400MHz, DMSO-d6)δ:10.42(s,1H),9.98(s,1H),9.04(s,1H),8.74(s,1H),8.44–8.42(m,2H),7.88(s,1H),7.67(d,J=8.3Hz,2H) ,7.55(d,J=9.0Hz,1H),7.29(d,J=8.3Hz,2H),6.77(d,J=5.3Hz,1H),2.34(t,J=7.5Hz,2H),2.04(t,J=7.5Hz,2H),1.87–1.80(m,2H). 13 C NMR(100MHz,DMSO-d6)δ:171.1,169.2,152.4,150.0,149.0,136.5,135.2,134. 3,128.1,125.2,124.8,124.4(2C),120.5(2C),118.5,101.6,36.1,32.1,21.6.

[0051] N 1 -Hydroxy-N4 -(4-((2-methylquinolin-4-yl)amino)phenyl)succinamide (I 16 ): yellow solid; yield: 70%; melting point: 233.8–234.5°C; 1 H NMR(400MHz, DMSO-d6)δ:10.07(s,1H),8.77(s,1H),8.32(d,J=8.4Hz,1H),7.77(d,J=8.3Hz,1H),7.70–7.60(m,3H), 7.44(t,J=7.6Hz,1H),7.29(d,J=8.6Hz,2H),6.66(s,1H),2.60(t,J=7.3Hz,2H),2.42(s,3H),2.32(t,J=7.3Hz,2H). 13 CNMR(100MHz,DMSO-d6)δ:170.5,168.8,159.1,149.0,148.9,136.1,135.8,129. 5,128.8,124.3(2×C),124.1,122.2,120.4(2×C),118.5,101.1,32.0,28.0,25.5.

[0052] N 1 -Hydroxy-N 5 -(4-((2-methylquinolin-4-yl)amino)phenyl)glutaramide (I 17 ): yellow solid; yield: 65%; melting point: 208.5–209.2°C; 1 H NMR (400MHz, DMSO-d6) δ: 10.00 (s, 1H), 8.78 (s, 1H), 8.32 (d, J = 8.4Hz, 1H), 7.77 (d, J = 8.4Hz, 1H), 7.67 (d, J = 8.3Hz, 2H), 7.62 (d, J = 7.9Hz, 1 H),7.43(t,J=7.6Hz,1H),7.29(d,J=8.3Hz,2H),6.67(s,1H),2.42(s,3H),2.34(t,J=7.5Hz,2H),2.04(t,J=7.4Hz,2H),1.88–1.80(m,2H). 13 C NMR(100MHz,DMSO-d6)δ:171.0,169.1,159.1,149.0,148.9,136.1,135.8,129.5,1 28.8,124.2(2×C),124.1,122.2,120.5(2×C),118.5,101.1,36.1,32.1,25.6,21.7.

[0053] N 1 -Hydroxy-N 8 -(4-((2-methylquinolin-4-yl)amino)phenyl)octanediamide (I 18 ): yellow solid; yield: 60%; melting point: 202.4–203.1°C; 1 H NMR(400MHz,DMSO-d6)δ:10.38(s,1H),9.96(s,1H),8.85(s,1H),8.34(d,J=8.4Hz ,1H),7.78(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,2H),7.64(t,J=7.6Hz,1H),7.44(t, J=7.9Hz,1H),7.29(d,J=8.4Hz,2H),6.67(s,1H),2.42(s,3H),2.32(t,J=7.5Hz,2 H),1.96(t,J=7.3Hz,2H),1.64–1.57(m,2H),1.55–1.48(m,2H),1.33–1.26(m,4H). 13 C NMR(100MHz,DMSO-d6)δ:171.5,169.6,158.9,149.2,148.5,136.3,135.6,129.7,128.4,12 4.4(2C),124.2,122.3,120.5(2C),118.4,101.1,36.8,32.7,28.9,28.9,25.6,25.5,25.3.

[0054] N 1 -Hydroxy-N 4 -(4-((2-methylquinolin-4-yl)amino)phenyl)terephthalamide (I 19 ): yellow solid; yield: 65%; melting point: 254.0–255.0°C; 1 H NMR (400MHz, DMSO-d6) δ: 10.63 (s, 1H), 8.58 (d, J = 8.3Hz, 1H), 8.10 (br s,3H),7.98–7.93(m,4H),7.79(t,J=7.7Hz,1H),7.57(t,J=7.6Hz,1H),7.44(d,J=8.3Hz,2H),6.71(s,1H),2.53(s,3H). 13C NMR(100MHz,DMSO-d6)δ:165.3,163.7,157.1,151.7,144.1,137.5,137.0,135.8,134.9,129.6 ,128.3(2×C),128.2,127.4(2×C),125.4,125.0(2×C),123.1,121.9(2×C),117.6,100.8,22.9.

[0055] N 1 -Hydroxy-N 6 -(4-((2-phenylquinolin-4-yl)amino)phenyl)adipamide (I 20 ): yellow solid; yield: 65%; melting point: 219.4–219.8°C; 1 H NMR (400MHz, DMSO-d6) δ: 10.36 (s, 1H), 9.93 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.36 (d, J = 8.4Hz, 1H), 7.95 (d, J = 7.4Hz, 2H), 7.90 (d, J=8.3Hz,1H),7.66(d-like,J=8.4Hz,3H),7.49–7.39(m,4H),7.34(d,J=8.4Hz,2H),7.25(s,1H),2.29(s,2H),1.96(s,2H),1.54(br s,4H). 13 C NMR(100MHz,DMSO-d6)δ:171.4,169.4,157.0,149.7,149.3,140.3,136.2,135.7,130.1,129.9,129 .4,129.1(2C),127.3(2C),124.9,124.3(2C),122.3,120.6(2C),119.1,98.2,36.7,32.6,25.3(2C).

[0056] Example 3: Cholinesterase inhibitory activity test

[0057] The inhibitory activity against electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was determined using the Ellman assay in a 96-well plate. All target compounds, as well as the reference drug rivastigmine (98% purity, Shanghai Bid Pharmaceuticals Co., Ltd.), were dissolved in dimethyl sulfoxide to prepare stock solutions and diluted with 0.1 M KH2PO4 / K2HPO4 buffer (PBS, pH 8.0) to a final assay concentration range of 0–32 μM. Briefly, in a 96-well plate, 140 μL of 0.1 M PBS buffer (pH 8.0), 20 μL of various concentrations of the test compound, 20 μL of AChE or BuChE (0.1 U / mL), and 10 μL of DTNB (10 mM, Ellman's reagent) were preincubated at 37°C for 15 minutes. After completion, 10 μL of substrate ATCI or BTCI (7.5 mM) was added and the mixture was incubated again at room temperature for 5 minutes. Subsequently, the absorbance was measured at 412 nm using a multifunctional microplate reader. The half-maximal inhibitory concentration (IC50) was calculated by the absorbance obtained at different concentrations of the test compound. 50 ) value. All tests were repeated three times. The results are shown in Table 2.

[0058] Table 2 Inhibitory activity of quinoline derivatives I containing hydroxamic acid fragments against cholinesterase

[0059]

[0060] As shown in Table 2, some of the quinoline derivatives containing hydroxamic acid fragments synthesized in the present invention have excellent cholinesterase inhibitory activity, among which compounds I4, I8, I 13 and I 18 IC for acetylcholinesterase 50 The values ​​were 3.71μM, 2.00μM, 1.61μM and 0.41μM, respectively, which were stronger than the positive control rivastigmine (IC 50 =5.26 μM). Compound I6 also exhibited a 1-fold greater inhibitory activity against butyrylcholinesterase than the positive control, rivastigmine. These results suggest that quinoline derivatives containing hydroxamic acid fragments are promising candidates for novel cholinesterase inhibitors as anti-Alzheimer's disease drugs.

[0061] Although the specific embodiments of the present invention have been described in detail in conjunction with the embodiments, this should not be construed as limiting the scope of protection of this patent. Within the scope described by the claims, various modifications and variations that can be made by those skilled in the art without creative work still fall within the scope of protection of this patent.

Claims

1. A quinoline derivative containing a hydroxamic acid fragment, the structure of which is shown in Formula I, in, R1 is selected from H, 7-Cl, 2-Me, 2-Ph; R2 is selected from -(CH2)2-, -(CH2)3-, -(CH2)6-, -C6H4-; R3 is selected from -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, -C6H4-; the quinoline derivative containing a hydroxamic acid fragment is selected from the following compounds:

2. The method for preparing a quinoline derivative containing a hydroxamic acid fragment according to claim 1, wherein: This is achieved by: Wherein, R1, R2 and R3 are defined the same as in claim 1.

3. The method for preparing a quinoline derivative containing a hydroxamic acid fragment according to claim 2, wherein: include: Step (a): using DMF as a reaction solvent, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and triethylamine as condensation agents, compound 1 and dicarboxylic acid monomethyl ester undergo condensation reaction to produce compound 2; Step (b): preparing a methanol solution of hydroxylamine using KOH and hydroxylamine hydrochloride in methanol, and then reacting compound 2 with the freshly prepared methanol solution of hydroxylamine to obtain a quinoline derivative I containing a hydroxamic acid fragment.

4. The method for preparing a quinoline derivative containing a hydroxamic acid fragment according to claim 3, wherein: include: In step (a), the molar ratio of compound 1, dicarboxylic acid monomethyl ester, triethylamine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1.1:1:3:1.1, and the reaction temperature is 70°C; In step (b), the molar ratio of compound 2, hydroxylamine hydrochloride and KOH is 0.1:1:1, the reaction temperature of hydroxylamine hydrochloride and KOH is 0°C, and the reaction temperature of compound 2 and hydroxylamine methanol solution is 45°C.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the quinoline derivative containing the hydroxamic acid fragment according to claim 1 as an active ingredient.

6. Use of the quinoline derivative containing a hydroxamic acid fragment according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of an anti-Alzheimer's disease drug.

7. The use according to claim 6, characterized in that The anti-Alzheimer's disease drug is a drug that inhibits the activity of cholinesterase.

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