CN107721923A - 4 N anilino quinolines class compound synthesis and the application for preparing anti-Alzheimer disease medicine - Google Patents

Abstract

The synthesis of 4-N-anilinoquinoline compounds and the application of preparing anti-Alzheimer's disease drugs, the synthesis method is, using acetone as a solvent, 6-methoxy-7-(3-chloropropoxy Base)-3-nitro-4-N-substituted anilino-quinoline was dissolved, morpholine was added dropwise, and then the temperature was raised for reaction, after the reaction was completed, cooled to room temperature, dried and purified to obtain the target compound. The 4-N-anilinoquinoline compounds include nine kinds, all of which have dual inhibitory activities of acetylcholinesterase and butyrylcholinesterase, have suitable lipophilicity, and can be used to prepare anti-Alzheimer's disease drugs , Open up a new way for the development of new drugs for the treatment of Alzheimer's disease.

Description

Synthesis of 4-N-anilinoquinoline compounds and preparation of anti-Alzheimer's disease drugs application

technical field

The invention relates to the technical field of preparation of anti-Alzheimer's disease drugs, in particular to the synthesis and application of 4-N-anilinoquinoline compounds.

technical background

In 2006, the International Conference on the Prevention of Dementia pointed out that there are more than 26 million Alzheimer's patients in the world, and 48% of the global Alzheimer's patients are in Asia. Alzheimer's disease (AD) is a neurodegenerative disease clinically manifested by continuous deterioration of cognition and memory, inability to move, and gradually being unable to take care of oneself. It is the most common type of senile dementia. . Currently clinically used anti-AD drugs are mainly acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine. These drugs increase the level of acetylcholine in the brain of patients by inhibiting the activity of acetylcholinesterase, thereby contributing to the Improve the patient's cognitive function and improve the behavioral disorder of the patient. Studies have found that there are two cholinesterases in the human brain, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). When the activity of AChE is inhibited, BChE can compensate for it. BChE has been widely accepted as the target of AD drugs, and the application of AChE and BChE diesterase inhibitors can better treat AD.

Quinoline derivatives and their analogs have a variety of physiological activities and are widely used clinically, such as pharmacological activities such as anti-tumor, anti-malarial, bacteriostatic and cholinesterase inhibition, among which tacrine has been used as an AChE inhibitor For the treatment of AD, the research on tacrine-based dyads and hybrids has also received extensive attention. In recent years, a large number of research results have shown that compounds containing 4-N-arylaminoquinoline structure have strong cholinesterase inhibitory effect and neuronal cell protection activity. The inventors found in previous studies that 4-N-anilinoquinoline compounds containing pyridine quaternary ammonium salt fragments have obvious dual inhibitory effects on AChE and BChE (Liu Yuming, Tian Lijun, Hu Dong, etc. Chemical Journal of Chinese Universities, 2017 ,38(3):392), but the lipophilicity of such compounds is poor, and the LopP value is less than 1, which will be unfavorable for oral absorption and blood-brain barrier penetration. Between 2 and 5.

Contents of the invention

The purpose of the present invention is to improve the lipophilicity of 4-N-anilinoquinoline compounds, and also to find novel cholinesterase inhibitor drugs. For this reason, the present invention replaces the water-soluble pyridinium quaternary ammonium salt fragments in the previous research with morpholine fragments, and synthesizes a series of 4-N-anilinoquinoline compounds containing morpholine fragments, in order to achieve the effect of improving lipophilicity. Subsequent studies on these 4-N-anilinoquinoline compounds found that nine compounds have good dual inhibitory effects on AChE and BChE, and show good lipophilicity, and have the potential to be developed into new anti-AD drugs. The prospect of the drug has opened up a new way for the development of new anti-Alzheimer's disease drugs and enriching the varieties of clinical drugs.

Technical scheme of the present invention:

4-N-anilinoquinoline compound, its chemical structural formula is as follows:

In the structural formula, R1 is phenyl, o _- chlorophenyl, m-chlorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, m-tolyl, m-methoxyphenyl, m-hydroxyphenyl or p-hydroxyl phenyl.

The compound includes 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-anilino-quinoline, 6-methoxy-7-( 3-N-morpholinopropoxy)-3-nitro-4-N-o-chloroanilino-quinoline, 6-methoxy-7-(3-N-morpholinopropoxy)- 3-nitro-4-N-m-chloroanilino-quinoline, 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-chloroaniline Base-quinoline, 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-(2,4-dichloroanilino)-quinoline, 6 -Methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-toluidinyl-quinoline, 6-methoxy-7-(3-N- Morpholinylpropoxy)-3-nitro-4-N-m-methoxyanilino-quinoline, 6-methoxy-7-(3-N-morpholinopropoxy)-3- Nitro-4-N-m-hydroxyanilino-quinoline and 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-hydroxyanilino- quinoline.

The preparation method of the 4-N-anilinoquinoline compound is that, using acetone as a solvent, substituting 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N- Anilino-quinoline was dissolved, and morpholine was added dropwise. After the dropwise addition, the temperature was raised for reaction. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain the target compound; the specific steps were as follows:

Step 1: Put vanillic acid into a container, add methanol to dissolve it completely, add concentrated hydrochloric acid, heat to reflux at 60-80°C, and react for 10-16 hours. After the reaction is completed, compound a, ie methyl vanillic acid, is obtained by purification.

Step 2: Dissolve compound a in a container with acetone, then add anhydrous potassium carbonate and 1-bromo-3-chloropropane, heat at 45-70°C for 10-16 hours. After the reaction was completed, it was filtered while hot, and the organic solvent was evaporated to dryness and purified to obtain compound b.

Step 3: Dissolve compound b in dichloromethane in a container, slowly add fuming nitric acid dropwise, and then react at room temperature for 3-8 hours. After the reaction was completed, excess fuming nitric acid was removed with aqueous sodium bicarbonate solution. The dichloromethane layer was separated with a separatory funnel, dried over anhydrous magnesium sulfate, and the compound c was obtained after evaporating the solvent.

Step 4: Dissolve compound c in ethanol in a round bottom flask, add saturated ammonium chloride aqueous solution after complete dissolution, then add iron powder, react at 50-80°C for 12 hours. After the reaction was completed, filter while hot with a funnel, and separate liquid extraction with dichloromethane. The organic solvent was evaporated to dryness, and compound d was obtained after purification by column chromatography.

Step 5: Dissolve compound d in a container with a small amount of methanol, then add 5wt% sodium hydroxide aqueous solution, heat up to 50-70°C, react for 10-16 hours, cool to room temperature, add hydrochloric acid to adjust the pH value to 2-3, Then it was extracted with dichloromethane. Compound e was obtained after evaporating the organic solvent to dryness.

Step 6: (1) Add compound e to distilled water and concentrated hydrochloric acid to form an aqueous solution of compound e. (2) Weigh sodium hydroxide and add twice the mass of water to dissolve it, add 1.0-2.0 times the equivalent of nitromethane at 25-30°C, raise the temperature to 40°C, keep 40-45°C and add the same amount of nitromethane as above again Methyl methane, after the addition, the temperature was raised to 50°C, kept at 50-55°C for 2-5 minutes, and then cooled to room temperature. Ice was then added, followed by hydrochloric acid and mixed well to form a reddish-brown solution. Add this reddish-brown solution to the aqueous solution of compound e to react at room temperature for 14-16 hours. Filter with suction, wash with distilled water until neutral, and dry to obtain compound f.

Step 7: Put compound f into a container, then add anhydrous acetic anhydride, heat to dissolve at 100°C, add anhydrous potassium acetate after the solution is clarified, reflux the oil bath for 15-30min, and cool down to room temperature. Filter, wash with glacial acetic acid, and then wash with water until neutral, and dry to obtain compound j.

Step 8: Put compound j into a container, slowly add phosphorus oxychloride, stir and reflux in an oil bath at 60-80°C for 5-10 hours. After the reaction was completed, excess phosphorus oxychloride was evaporated, and dichloromethane was added to dissolve the product, and then cold saturated aqueous potassium carbonate solution was added. After stirring in an ice bath for half an hour, the dichloromethane layer was separated with a separatory funnel, washed twice with water, and dried over anhydrous magnesium sulfate to obtain compound h.

Step 9: Put compound h into a container, then add isopropanol, and heat to dissolve. Add anilines containing different substituents and react at 82-100°C for 5-9 hours. After the reaction is completed, place it at room temperature until a precipitate precipitates, filter, wash with water, and dry with anhydrous magnesium sulfate to obtain 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-substituted aniline base-quinoline compounds.

Step 10: Dissolve the 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-substituted anilino-quinoline compound obtained in step 9 in acetone, and add 1.0~ 5.0 times the equivalent of morpholine. After the dropwise addition, the temperature was raised to 45-70°C, and the reaction was kept for 10-20 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain the target compound.

The 4-N-anilinoquinoline compound provided by the invention has dual inhibitory activity of acetylcholinesterase and butyrylcholinesterase, and can be used for preparing anti-Alzheimer's disease medicine.

Advantage and beneficial effect of the present invention are:

4-N-anilinoquinoline compounds have good anti-AChE and BChE activities, and have suitable lipophilicity, which has opened up a new way for the development of new anti-AD drugs and enriching clinical drug varieties; the synthesis of such morpholines In the process of the group-substituted compound, the bibliographical reports use acetonitrile as a solvent. Considering that acetonitrile is a second-class solvent and has carcinogenicity, the present invention uses acetone, a third-class solvent that can be used for pharmaceutical production, to achieve the purpose of synthesis as a reaction solvent. There is no literature on this synthetic improvement.

detailed description

In order to find anti-Alzheimer's disease drugs with better efficacy, combined with the current understanding of anti-Alzheimer's disease drugs, according to literature reports and the results of years of research work in the applicant's laboratory, multiple 4-N-anilino groups were synthesized Quinoline compounds were screened for cholinesterase inhibition of the obtained target compounds, and nine of them were found to have good dual inhibitory activities of acetylcholinesterase and butyrylcholinesterase, and had suitable lipophilicity. The structure of the target compound has been confirmed by high-resolution mass spectroscopy (HR-ESI-MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR).

Example 1:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-anilino-quinoline, the steps are as follows:

Step 1: Put 1 g of vanillic acid (5.95 mmol) into a 50 mL round bottom flask, add 10 mL of methanol until completely dissolved, then add 0.6 mL of concentrated hydrochloric acid, heat to reflux at 70°C, and react for 12 hours. After the reaction was completed, 0.87 g of compound a, ie methyl vanillic acid, was purified to obtain 0.87 g, with a yield of 87%. The mass of this compound is accumulated in multiple reactions.

Step 2: Dissolve 1g (5.5mmol) of compound a in a 50mL round bottom flask with acetone, then add 1.5g of anhydrous potassium carbonate and 1.2g (8.7mml) of 1-bromo-3-chloropropane, and heat at 65°C Reflux for 12 hours. After the reaction was completed, it was filtered while hot, and the organic solvent was evaporated to dryness and purified to obtain 0.74 g of compound b with a yield of 74%. The mass of this compound is accumulated in multiple reactions.

Step 3: Dissolve 1g (3.88mmol) of compound b in a 50mL round bottom flask with dichloromethane, slowly add 0.14mL (7.75mmol) fuming nitric acid dropwise, and then react at room temperature for 5 hours. After the reaction was completed, excess fuming nitric acid was removed with aqueous sodium bicarbonate solution. The dichloromethane layer was separated with a separatory funnel, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 0.862 g of compound c with a yield of 86.2%. The mass of this compound is accumulated in multiple reactions.

Step 4: Dissolve 1 g of compound c in ethanol in a round bottom flask, add saturated ammonium chloride aqueous solution after complete dissolution, then add 1.3 g (0.023 mol) iron powder, and react at 70° C. for 12 hours. After the reaction was completed, filter while hot with a funnel, and separate liquid extraction with dichloromethane. The organic solvent was evaporated to dryness, and 0.87 g of compound d was obtained after purification by column chromatography, with a yield of 87%. The mass of this compound is accumulated in multiple reactions.

Step 5: Dissolve 1g (3.66mmol) of compound d in a 50mL round bottom flask with a small amount of methanol, then add 6.1mL of 5wt% sodium hydroxide aqueous solution, heat up to 50°C, react for 12 hours, cool to room temperature, add hydrochloric acid to adjust pH value to 2-3, and then extracted with dichloromethane. After evaporating the organic solvent to dryness, 0.85 g of compound e was obtained with a yield of 85%. The mass of this compound is accumulated in multiple reactions.

Step 6: (1) 1 g (3.86 mmol) of compound e was added to 4.8 mL of distilled water and 0.29 mL of concentrated hydrochloric acid to form an aqueous solution of compound e. (2) Weigh 0.52g (0.013mol) of sodium hydroxide and add 1.04mL of water to dissolve, add 0.26g (4.25mmol) of nitromethane at 30°C, raise the temperature to 40°C, keep 40°C and add 0.26g (4.25mL) mmol) nitromethane, after the addition, the temperature was raised to 50° C., kept at 50° C. for 5 minutes, and then cooled to room temperature. Ice was then added, followed by 1.16 ml of hydrochloric acid and mixed well to form a reddish-brown solution. This reddish-brown solution was added to the aqueous solution of compound e to react at room temperature for 16 hours. Suction filtration, washing with distilled water until neutral, and drying gave 0.82 g of compound f with a yield of 82%. The mass of this compound is accumulated in multiple reactions.

Step 7: Put 1g (3.03mmol) of compound f into a 50mL round bottom flask, then add 3mL of anhydrous acetic anhydride, heat to dissolve at 100°C, add 0.3g (3.03mmol) of anhydrous potassium acetate after the solution is clarified, and put in an oil bath Reflux for 15 minutes and cool down to room temperature. Filtered, washed with glacial acetic acid, and then washed with water until neutral, and dried to obtain 0.21 g of compound j with a yield of 21%. The mass of this compound is accumulated in multiple reactions.

Step 8: Put 1 g (3.19 mmol) of compound j into a 50 mL round bottom flask, slowly add 5.14 mL of phosphorus oxychloride, stir and reflux in an oil bath at 70°C for 8 hours. After the reaction was completed, excess phosphorus oxychloride was evaporated, and dichloromethane was added to dissolve the product, and then cold saturated aqueous potassium carbonate solution was added. After stirring in an ice bath for half an hour, the dichloromethane layer was separated with a separatory funnel, washed twice with water, and dried over anhydrous magnesium sulfate to obtain 0.89 g of compound h with a yield of 89%.

Step 9: Put 0.5 g (1.515 mmol) of compound h into a 50 mL round bottom flask, then add 10 mL of isopropanol, and heat to dissolve. 1.515 mmol of aniline was added, and the reaction was refluxed at 90° C. for 6 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.455 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -Anilino-quinoline, 91% yield.

Step 10: Dissolve 0.45 g (1.16 mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-anilino-quinoline in 5 mL of acetone, and add 1.5 Double the equivalent of morpholine, after the dropwise addition, the temperature was raised to 60°C and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.5 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-anilino-quinoline , namely compound 1, the yield was 88.89%.

The structure of compound 1 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp150-152℃; IR(KBr)cm ^-1 : 3424, 2956, 1573, 1525, 1483, 1282, 1260, 1221, 1104; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.10(m, 2H), 2.56(t, J＝7.0Hz, 2H), 3.16(m, 4H), 3.34(s, 3H), 3.94(m, 4H), 4.26(t, J＝6.6Hz, 2H), 6.89(s, 1H), 7.19( d,J=7.8Hz,2H),7.26(t,J=7.8Hz,1H),7.36(s,1H),7.41(t,J=7.8Hz,2H),9.36(s,1H),10.42( s, 1H, NH); ¹³ C-NMR (100MHz, CDCl ₃ ): 25.9, 53.7 (2C), 55.2 (2C), 66.9 (2C), 67.4, 106.4, 110.0, 112.7, 124.0 (2C), 126.0, 128.6, 129.7(2C), 141.2, 145.0, 145.3, 148.0, 148.3, 153.6; HR-ESI-MS(positivemode) m/z439.1992[M+H] ⁺ (calcd439.1981forC ₂₃ H ₂₇ N ₄ O ₅ ) .

Example 2:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-o-chloroanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is substantially the same as in Example 1 except that the amount is used.

Step 9: Put 0.6 g (1.82 mmol) of compound h obtained in Step 8 into a 50 mL round bottom flask, then add 10 mL of isopropanol, and heat to dissolve. 1.82 mmol of o-chloroaniline was added, and the reaction was refluxed at 90° C. for 6 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.52 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -O-chloroanilino-quinoline, yield 86%.

Step 10: Dissolve 0.5g (1.19mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-o-chloroanilino-quinoline in 6mL of acetone, drop Add 3.5 times the equivalent of morpholine, raise the temperature to 45°C, and react for 20 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.43 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-o-chloroanilino- The yield of quinoline, namely compound 2, was 86%.

The structure of compound 2 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp154-156℃; IR(KBr)cm ^-1 : 3421, 2961, 1576, 1523, 1489, 1428, 1261, 1104; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.13(m, 2H), 2.59(t, J= 7.04Hz, 2H), 3.25(m, 4H), 3.45(s, 3H), 3.99(m, 4H), 4.24(t, J=6.6Hz, 2H), 6.86(s, 1H), 7.03(d, J=7.8Hz, 1H), 7.16(s, 1H), 7.20(d, J=8.12Hz, 1H), 7.40(s, 1H), 9.37(s, 1H), 10.21(s, 1H, NH); ¹³ C-NMR (100MHz, CDCl ₃ ): 153.9, 148.8, 148.2, 144.9, 143.8, 142.5, 135.3, 130.5, 129.3 (2C), 125.5 (2C), 123.1, 121.2, 112.8, 110.0, 105.9, 67.5 (2C ), 55.4, 55.2 (2C), 25.8; HR-ESI-MS (positive mode) m/z 473.1604 [M+H] ⁺ (calcd 473.1591 for C ₂₃ H ₂₆ Cl ₁ N ₄ O ₅ ).

Example 3:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-chloroanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 0.66 g (2 mmol) of compound h into a 50 mL round bottom flask, then add 16 mL of isopropanol, and heat to dissolve. 3.03 mmol of m-chloroaniline was added, and the reaction was refluxed at 100° C. for 5 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.57 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -m-chloroanilino-quinoline, yield 87%.

Step 10: Dissolve 0.55g (1.31mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-m-chloroanilino-quinoline in 9mL of acetone, drop Add 2.0 equivalents of morpholine, raise the temperature to 58°C, and react for 16 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.48 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-chloroanilino- Quinoline, ie compound 3, has a yield of 87.27%.

The structure of compound 3 was confirmed by high-resolution mass spectroscopy (HR-ESI-MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance ( ¹ H-NMR), and carbon nuclear magnetic resonance ( ¹³ C-NMR): mp142-144℃; IR(KBr)cm ^-1 : 3420, 3286, 3037, 1561, 1488, 1430, 1307, 1103, 1044; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.12(m, 2H), 2.59(t, J＝7.1Hz, 2H), 3.23(m, 4H), 3.41(s, 3H), 3.99(m, 4H), 4.27(t, J＝6.6Hz, 2H), 6.78(s, 1H), 6.99( d,J=7.6Hz,1H),7.20(m,2H),7.39(s,1H),7.55(t,J=7.6Hz,1H),9.37(s,1H),10.15(s,1H,NH ); ¹³ C-NMR (100MHz, CDCl ₃ ): 25.8, 53.6 (2C), 55.2, 55.4, 66.8 (2C), 67.4, 105.2, 110.0, 113.2, 124.4, 126.4, 127.4, 128.1, 129.5, 130.5, 138.4 , 143.9, 145.0, 148.0, 148.9, 153.9; HR-ESI-MS (positive mode) m/z 473.1604 [M+H] ⁺ (calcd 473.1592 for C ₂₃ H ₂₆ ClN ₄ O ₅ ).

Example 4:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-chloroanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 0.88g (2.67mmol) of compound h into a 50mL round bottom flask, then add 8mL of isopropanol, and heat to dissolve. 2.67 mmol of p-chloroaniline was added, and the reaction was refluxed at 90° C. for 5 hours. After the reaction is completed, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry with anhydrous magnesium sulfate to obtain 0.80 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N - p-chloroanilino-quinoline, yield 91%.

Step 10: Dissolve 0.80 g (1.64 mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-p-chloroanilino-quinoline in 11 mL of acetone, drop Add 2.5 times the equivalent of morpholine, raise the temperature to 70°C, and react for 10 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.71 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-chloroanilino- The yield of quinoline, namely compound 4, was 88.75%.

The structure of compound 4 was confirmed by high-resolution mass spectroscopy (HR-ESI-MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance ( ¹ H-NMR), and carbon nuclear magnetic resonance ( ¹³ C-NMR): mp260-262℃; IR(KBr)cm ^-1 : 3421, 3315, 2360, 1569, 1521, 1468, 1287, 1256, 1104; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.12(m, 2H), 2.59(t, J＝7.0Hz, 2H), 3.20(m, 4H), 3.43(s, 3H), 3.98(m, 4H), 4.26(t, J＝6.48Hz, 2H), 6.83(s, 1H), 7.10( d, J=8.4Hz, 2H), 7.29(s, 1H), 7.37(d, J=2.80Hz, 2H), 9.36(s, 1H), 10.22(s, 1H, NH); ¹³ C-NMR ( 100MHz, CDCl ₃ ):25.8,53.7(2C),55.3(2C),64.6,66.9(2C),105.9,110.0,112.7,124.7(2C),129.1,129.7(2C),131.1,139.9,144.3,145.0 , 148.1, 148.7, 153.9; HR-ESI-MS (positive mode) m/z 473.1596 [M+H] ⁺ (calcd 473.1591 for C ₂₃ H ₂₆ ClN ₄ O ₅ ).

Example 5:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-(2,4-dichloroanilino)-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 1 g (3.03 mmol) of compound h into a 50 mL round bottom flask, then add 12 mL of isopropanol, and heat to dissolve. 3.03 mmol of 2,4-dichloroaniline was added, and the reaction was refluxed at 90° C. for 5 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.92 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -(2,4-Dichloroanilino)-quinoline, 92% yield.

Step 10: Add 0.90 g (1.98 mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-(2,4-dichloroanilino)-quinoline Dissolve it in 13 mL of acetone, add 2.0 equivalents of morpholine dropwise, raise the temperature to 63°C, and react for 14 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.82 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-(2,4- Dichloroanilino)-quinoline, namely compound 5, the yield was 91.11%.

The structure of compound 5 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp127-129℃; IR(KBr)cm ^-1 : 3419, 3047, 1579, 1513, 1483, 1430, 1283, 1258; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.18(m, 2H), 2.60(t, J= 7.04Hz, 2H), 3.24(m, 4H), 3.51(s, 3H), 3.99(m, 4H), 4.28(t, J=6.56Hz, 2H), 6.73(s, 1H), 6.84(d, J＝8.64Hz, 1H), 7.17(dd, J＝2.24, 2.2Hz, 1H), 7.42(s, 1H), 7.58(d, J＝2.08Hz, 1H), 9.38(s, 1H), 10.00( s, 1H, NH); ¹³ C-NMR (100MHz, CDCl ₃ ): 25.7, 55.2, 55.5, 64.1, 65.5, 104.8, 110.1 (2C), 113.2, 116.3, 124.2, 127.4, 127.6, 128.1, 128.9, 130.0 , 130.6, 137.2, 143.1, 144.8, 148.1, 149.2, 154.1; HR-ESI-MS (positivemode) m/z 507.1201 [M+H] ⁺ (calcd 507.1202 for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₅ ).

Embodiment 6:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-toluidinyl-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 0.64g (1.94mmol) of compound h into a 50mL round bottom flask, then add 8mL of isopropanol, and heat to dissolve. 1.94 mmol of m-toluidine was added, and the reaction was refluxed at 90° C. for 6 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.57 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -m-toluidino-quinoline, yield 89%.

Step 10: Dissolve 0.55 g (1.375 mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-m-toluidinyl-quinoline in 7 mL of acetone, drop Add 1.0 equivalent of morpholine, raise the temperature to 60°C, and react for 12 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.46 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-toluidine- Quinoline, namely compound 6, has a yield of 83.64%.

The structure of compound 6 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp121-123℃; IR(KBr)cm ^-1 : 3420, 2959, 2360, 1578, 1523, 1492, 1284, 1261, 1209, 1103; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.12(m, 2H), 2.35( s,3H),2.58(t,J=7.2Hz,2H),3.20(m,4H),3.36(s,3H),3.96(m,4H),4.26(t,J=7.2Hz,2H), 6.93(s,1H),7.00(d,J=8.0Hz,1H),7.03(s,1H),7.07(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H), 7.36(s,1H),9.36(s,1H),10.43(s,1H,NH); ¹³ C-NMR(100MHz,CDCl ₃ ):21.3,25.8,53.7(2C),55.2,55.3,66.9(2C ),67.4,106.6,110.0,112.7,121.1,124.7,126.9,128.4,129.5,139.9,141.0,145.1,145.4,148.0,148.2,153.6; HR-ESI-MS(positivemode)m/z453.2169[M+ H] ⁺ (calcd453.2138 for C ₂₄ H ₂₉ N ₅ O ₄ ).

Embodiment 7:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-methoxyanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 0.75g (2.27mmol) of compound h into a 50mL round bottom flask, then add 12mL of isopropanol, and heat to dissolve. 2.27 mmol of m-methoxyaniline was added, and the reaction was refluxed at 90° C. for 6 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.645 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -m-Methoxyanilino-quinoline, 86% yield.

Step 10: Dissolve 0.6 g (1.44 mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-m-methoxyanilino-quinoline in 10 mL of acetone , adding 5.0 equivalents of morpholine, raising the temperature to 64°C, and reacting for 10 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.49 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-methoxyaniline Base-quinoline, namely compound 7, the yield was 81.67%.

The structure of compound 7 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp169-171℃; IR(KBr)cm ^-1 : 3417, 2444, 2360, 1572, 1522, 1454, 1428, 1286, 1103; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.12(m, 2H), 2.56(t, J＝7.04Hz, 2H), 3.23(m, 4H), 3.40(s, 3H), 3.77(s, 3H), 4.00(m, 4H), 4.24(t, J＝6.6Hz, 2H), 6.72( s,1H),6.78(dd,J=8.36,8.0Hz,1H),6.96(s,1H),7.27(d,J=3.52Hz,2H),7.37(s,1H),9.36(s,1H ),10.36(s,1H,NH); ¹³ C-NMR(100MHz,CDCl ₃ ):160.7,153.5,148.2,147.9,145.2,144.8,142.2,130.3,128.5,116.1,112.8,111.5,109.8,109.6, 106.3, 67.366.7, 64.1, 55.5, 55.3, 55.2, 53.6, 43.5, 25.7; HR-ESI-MS (positivemode) m/ _z469.2087 [ _{M +} H] ⁺ ( _{calcd469.2087forC24H29N4O6} ).

Embodiment 8:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-hydroxyanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 0.71 g (2.15 mmol) of compound h into a 50 mL round bottom flask, then add 12 mL of isopropanol, and heat to dissolve. 2.15 mmol of m-hydroxyaniline was added, and the reaction was refluxed at 82° C. for 9 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.47 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -m-Hydroxyanilino-quinoline, 66% yield.

Step 10: Dissolve 0.45g (1.12mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-m-hydroxyanilino-quinoline in 5mL of acetone, drop Add 4.0 times the equivalent of morpholine, raise the temperature to 61°C, and react for 11 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.34 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-m-hydroxyanilino- Quinoline, namely compound 8, has a yield of 75.56%.

The structure of compound 8 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp81-83℃; IR(KBr)cm ^-1 : 3417, 2444, 1618, 1455, 1432, 1286, 1104; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.07(m, 2H), 2.55(t, J=6.96Hz ,2H),3.40(m,4H),3.50(s,3H),3.89(m,4H),4.21(t,J＝6.32Hz,2H),5.32(s,2H),6.56(s,1H) ,6.78(d,J=6.8Hz,2H),6.98(s,1H),7.24(t,J=7.8Hz,1H),9.28(s,1H),10.30(s,1H, ^NH ); -NMR (100MHz, CDCl ₃ ): 158.3, 153.6, 148.2, 147.6, 145.1, 144.9, 142.1, 130.5, 128.4, 115.1, 113.5, 112.8, 111.1, 109.4, 106.5, 67.4, 66.8, 65.2, 55.3, , 44.3, 25.8; HR-ESI-MS (positive mode) m/z 455.1946 [M+H] ⁺ (calcd 455.1930 for C ₂₃ H ₂₇ N ₄ O ₆ ).

Embodiment 9:

The preparation of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-hydroxyanilino-quinoline, the steps are as follows:

The preparation method of eight steps from step 1 to step 8 is basically the same as that of Example 1.

Step 9: Put 1 g (3.03 mmol) of compound h into a 50 mL round bottom flask, then add 12 mL of isopropanol, and heat to dissolve. 3.03 mmol of p-hydroxyaniline was added, and the reaction was refluxed at 90° C. for 7 hours. After the reaction is complete, place it at room temperature until a precipitate precipitates out, filter, wash with water, and dry over anhydrous magnesium sulfate to obtain 0.79 g of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N -p-Hydroxyanilino-quinoline in 79% yield.

Step 10: Dissolve 0.75g (1.86mmol) of 6-methoxy-7-(3-chloropropoxy)-3-nitro-4-N-p-hydroxyanilino-quinoline in 10mL of acetone, drop Add 3.0 equivalents of morpholine, raise the temperature to 55°C, and react for 18 hours. After the reaction was completed, it was cooled to room temperature, dried and purified to obtain 0.59 g of 6-methoxy-7-(3-N-morpholinopropoxy)-3-nitro-4-N-p-hydroxyanilino- Quinoline, that is, compound 9, has a yield of 78.67%.

The structure of compound 9 was confirmed by high-resolution mass spectrometry (HR-ESI-MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectrum ( ¹ H-NMR), and carbon nuclear magnetic resonance spectrum ( ¹³ C-NMR): mp161-163℃; IR(KBr)cm ^-1 : 3256, 2957, 1586, 1508, 1264, 1153, 1115; ¹ H-NMR (400MHz, CDCl ₃ ): δ2.09(m, 2H), 2.51(m, 4H), 2.58 (t,J=7.34Hz,2H),3.38(s,3H),3.94(m,4H),4.21(t,J=6.26Hz,2H),6.88(s,1H),7.00(s,1H) , 7.10 (d, J=8.52Hz, 2H), 7.25 (s, 1H), 9.29 (s, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ): 25.7, 45.8, 48.5, 48.7, 49.5, 49.7, 53.1, 55.3, 67.2, 67.6, 106.6, 109.3, 112.3, 116.3, 126.4, 127.1, 132.3, 145.4, 146.2, 147.3, 147.8, 153.4, 155.9; HR-ESI-MS (positivemode) m/z455.1948[M+ H] ⁺ (calcd 455.1930 for C ₂₃ H ₂₇ N ₄ O ₆ ).

Cholinesterase inhibitory activity assay

The compound that above embodiment makes is screened to the inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE):

AChE and BChE inhibitory activity assays were performed using the modified Ellman method. Add 140 μL of phosphate buffer (100 mmol/L), AChE (20 μL, 0.05 U/mL) or BChE (20 μL, 0.05 U/mL) and 20 μL of the compound to be tested in sequence in a 96-well plate, mix well and place at 25 °C Incubate in an incubator for 15 minutes. Then add 10μL NTB (10.0mmol/L) and ATCI (10μL, 7.5mmol/L) or BTCI (10μL, 7.5mmol/L), and then put it in an incubator, and after incubating at 37°C for 30min, use a microplate reader to The light absorption value (OD) of each well was measured at a wavelength of 412nm. 20 μL of galantamine was used instead of the test compound as a positive control, and 20 μL of phosphate buffer (100 mmol/L) was added to the blank group to replace the test compound. Each set of data was performed 3 times in parallel, and the average value was taken. Record the results and calculate the inhibition rate according to the formula [inhibition rate (%) = (OD blank - OD sample) / OD blank × 100%], and calculate the half inhibitory concentration IC ₅₀ value. The results of the activity assay are shown in Table 1:

Table 1 cholinesterase inhibitory activity results

drug-like evaluation

The lipophilicity of the compound that above embodiment makes is calculated as follows through ChemDraw software:

The LogP value of each compound of table 2

Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 LogP value 3.41 4.03 4.03 4.03 4.65 3.83 3.54 3.02 3.02

The test results in Table 1 show that these compounds have a good inhibitory effect on acetylcholinesterase and butyrylcholinesterase, and the results in Table 2 show that the lipophilicity of these compounds meets the drug-like LogP index of anti-AD drugs, and has the potential to be used in the preparation of anti-AD drugs. The promise of Alzheimer's disease drugs.

The above content is only a representative embodiment of the present invention, and does not limit the present invention in any form. Any modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention still fall within the scope of the technical solutions of the present invention.

Claims (6)

1.4-N- anilino quinolines class compounds, it is characterised in that its chemical structural formula is as follows：

R in structural formula₁For phenyl, Chloro-O-Phenyl, a chlorphenyl, rubigan, 2,4 dichloro benzene base, a tolyl, meta-methoxy Phenyl, a hydroxy phenyl or p-hydroxybenzene.

2. 4-N- anilino quinolines class compound as claimed in claim 1, it is characterised in that：The compound specifically includes 6- Methoxyl group -7- (3-N- morpholinopropoxies) -3- nitro -4-N- aniline yl-quinoline, the 6- methoxyl groups -7- (oxygen of 3-N- morpholinyls third Base) -3- nitro -4-N- o-chloranilines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- m-chloros Aniline yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- parachloroanilinum yl-quinoline, 6- methoxies Base -7- (3-N- morpholinopropoxies) -3- nitros -4-N- (2,4 dichloro benzene amido)-quinoline, 6- methoxyl groups -7- (3-N- morpholines Base propoxyl group) -3- nitro -4-N- meta-aminotoluenes yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4- Hydroxy benzenes amido between N- m-anisidines yl-quinoline, 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitros -4-N- - Quinoline and 6- methoxyl groups -7- (3-N- morpholinopropoxies) -3- nitro -4-N- para hydroxybenzene amine yl-quinolines.

A kind of 3. synthetic method of 4-N- anilino quinolines class compounds as claimed in claim 1, it is characterised in that：Using acetone as Solvent, reaction system is carried out by 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines and morpholine It is standby to form, comprise the following steps that：

By 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines with acetone solution, morphine is added dropwise Quinoline, heat up and reacted after being added dropwise, be cooled to room temperature after completion of the reaction, dry purifying, obtain target compound.

4. the synthetic method of 4-N- anilino quinolines class compound according to claim 3, it is characterised in that：The 6- methoxies Base -7- (3- chlorine propoxyl group) -3- nitro -4-N- substituted anilines yl-quinoline be 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros - 4-N- aniline yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- o-chloranilines yl-quinoline, 6- methoxyl groups - 7- (3- chlorine propoxyl group) -3- nitro -4-N- m-chloroanilines yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- Parachloroanilinum yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- (2,4 dichloro benzene amido)-quinoline, 6- first Epoxide -7- (3- chlorine propoxyl group) -3- nitro -4-N- meta-aminotoluenes yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitre Hydroxy benzenes amido-quinoline between base -4-N- m-anisidines yl-quinoline, 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitros -4-N- Quinoline or 6- methoxyl groups -7- (3- chlorine propoxyl group) -3- nitro -4-N- para hydroxybenzene amine yl-quinolines.

5. according to the synthetic method of the 4-N- anilino quinolines class compound of claim 3 or 4, it is characterised in that：The 6- The mol ratio of methoxyl group -7- (3- chlorine propoxyl group) -3- nitros -4-N- substituted anilines yl-quinolines and morpholine is 1:1.0-5.0； After being added dropwise, 10~20h of insulation reaction, holding temperature is 45~70 DEG C.

6. the application of the 4-N- anilino quinolines class compounds described in claim 1 or 2, it is characterised in that：Described compound With the double activity suppressed of acetylcholinesterase and butyrylcholine esterase, lipophilicity is suitable, available for preparing anti-Alzheimer Sick class medicine.