1-phenyl-pyrroloisoquinoline-3-one compounds and preparation methods and applications thereof

Abstract

The present invention provides a 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound, a preparation method and an application thereof. The structural formula of the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound is shown as general formula I, wherein R1 and R2 are selected from hydrogen, methoxy, fluorine, bromine, and hydroxyl, and R1 and R2 are the same or different; R1 is located at any one or two of the ortho, meta, and para positions of the benzene ring, and R2 is located at the 7-position and / or 8-position of the benzene ring; including the formed cis-trans isomers. Through the screening studies on the NMDA-induced PC12 cell injury protection activity and the antidepressant activity in mice, it is shown that the compounds of the present invention can be used for the preparation of drugs for neurodegenerative diseases, especially depression.

Description

Technical Field

[0001] The present invention belongs to the technical field of compounds and their synthesis and application, and specifically relates to 1-phenyl-pyrroloisoquinoline-3-one compounds, namely 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds, and preparation methods and applications thereof. Background Art

[0002] Depression is a type of mental illness characterized by mood disorders, which is caused by external environment and psychological quality, and is accompanied by clinical symptoms such as loss of interest, decreased energy, slow movements, loss of appetite or weight, etc. In clinical applications, there are many drugs available for antidepressant use, such as amitriptyline, clomipramine, moclobemide, fluoxetine, paroxetine, sertraline, citalopram, etc. Although these drugs can be used to treat or relieve the pain of patients with various depressions to varying degrees, they have side effects and make people feel uncomfortable, thus limiting their long-term use. In order to eliminate or reduce toxic side effects and improve the therapeutic effect, new compounds with new structural characteristics and new mechanisms of action are needed.

[0003] Existing research results have shown that enhancing neural plasticity is an important therapeutic pathway for antidepressant drugs to exert their effects. By regulating glutamate NMDA (N-methyl-D-aspartate) receptors, the calcium / calmodulin-dependent protein kinase II (CaMKⅡ) pathway and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors can be activated, and synaptic plasticity and phosphorylation of cyclic AMP response element binding protein can be enhanced, which can produce a rapid antidepressant effect. Compounds that act on the glutamate binding site, glycine binding site, and ion channel site on glutamate NMDA receptors and have an antagonistic effect on NMDA receptors have a rapid antidepressant effect. It can be seen that regulating NMDA receptors, activating AMPA receptors, and enhancing neural plasticity are rapid and long-term antidepressant pathways. Summary of the invention

[0004] The purpose of the present invention is to provide a 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound and a preparation method thereof, as well as the use of the compound in the preparation of a drug for treating neurodegenerative diseases, especially depression, and is expected to provide a new antidepressant drug.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound, the structural formula of which is shown in general formula I:

[0007]

[0008] Where R 1 , R 2 is selected from hydrogen, methoxy, fluorine, bromine, hydroxyl, R 1 With R 2 Same or Different; R 1 Located at any one or two of the ortho, meta, or para positions of the benzene ring, R 2 Located at position 7 and / or position 8; including the cis and trans isomers formed.

[0009] The aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound, in the general formula I, R 1 is selected from hydrogen, methoxy, fluorine, bromine, R 2 is selected from hydrogen, methoxy, hydroxyl, R 1 Located in any of the ortho, meta, or para positions of the benzene ring, R 2 Located at position 7 and / or 8.

[0010] The aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound, wherein the compound is the following W1-W18:

[0011]

[0012] The preparation method of the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound described in any one of the above items comprises the following steps: (1) dissolving the compound represented by the general formula II in formaldehyde, adding potassium carbonate and reacting under stirring at room temperature to obtain an intermediate represented by the general formula Ш; (2) sequentially adding PPA (polyphosphoric acid), 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш, and reacting under reflux under nitrogen protection to obtain the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound I; the reaction route is as follows:

[0013]

[0014] The preparation method of the aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds comprises the following steps: in step (1), the compound represented by the general formula II is dissolved in formaldehyde, potassium carbonate is slowly added under stirring at room temperature, and after the addition is completed, the reaction is continued under stirring at room temperature overnight. After the reaction is completed, the obtained reaction solution is dispersed with water, extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure and then separated and purified to obtain the intermediate represented by the general formula Ш.

[0015] The preparation method of the aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound, in step (1), the compound represented by general formula II, formaldehyde and potassium carbonate are added in a ratio of 0.1 mmol:3 mL:0.5 mmol.

[0016] The preparation method of the aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound comprises the following steps: in step (2), PPA, 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш are added in sequence, and the mixture is refluxed for 3 hours under nitrogen protection. After the reaction is completed, the obtained reaction solution is dispersed with water, extracted twice with ethyl acetate, and the pH of the organic layer is adjusted to 7.0 with a saturated sodium bicarbonate solution. The mixture is concentrated under reduced pressure and then separated and purified to obtain 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound I.

[0017] The preparation method of the aforementioned 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds, in step (2), PPA, 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш are added in a ratio of 0.01 mmol: 2 mL: 0.4 mL: 0.1 mmol.

[0018] Use of any of the above 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds in the preparation of drugs for treating neurodegenerative diseases.

[0019] Use of any of the above 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds in the preparation of drugs for treating depression.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention discloses for the first time 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds and their preparation method and application. Through the screening test of the protective activity against NMDA-induced PC12 cell damage, it is proved that it can be used for the treatment of neurodegenerative diseases; through the in vitro antidepressant activity study on mice of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound W1, it is found that it has an antidepressant effect, and Nissl staining finds that W1 has a protective effect on mouse hippocampal neurons, suggesting that 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds can be used for the preparation of antidepressant drugs, and is expected to provide a new antidepressant drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The results of MTT assay of cell activity of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds on NMDA-induced PC12 cell injury;

[0023] Figure 2 Results of the forced swimming test for the in vivo antidepressant activity screening protocol W1 in mice;

[0024] Figure 3 Results of the W1 tail suspension test for in vivo antidepressant activity screening in mice;

[0025] Figure 4 Results of the open field test for the in vivo antidepressant activity screening program W1 in mice;

[0026] Figure 5 Results of the in vivo antidepressant activity screening program W1 on the hippocampal neurons of anxious mice induced by chronic stress (Nissl staining); K: blank group; M: model group; A: amitriptyline group; D: W1 low-dose group; Z: W1 medium-dose group; G: W1 high-dose group. DETAILED DESCRIPTION

[0027] The compound of general formula II used in the present invention can be prepared according to the method in CN1120036A or CN1040747C.

[0028] Example 1: The preparation method of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds is as follows:

[0029] (1) Add 0.2 mmol of the compound of formula II to a flask, add 6 mL of formaldehyde to dissolve the compound of formula II, slowly add 1 mmol of potassium carbonate under stirring at room temperature, continue stirring at room temperature after the addition is complete, and react overnight; after the reaction is completed, the reaction solution is dispersed with water, extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure and separated and purified to obtain the intermediate represented by the general formula Ш; (2) Add 0.025 mmol of PPA to another flask, then add 5 mL of 36.5% concentrated hydrochloric acid, then add 1 mL of anhydrous ethanol, and then add 0.25 mmol of the intermediate represented by the general formula Ш, and reflux for reaction under nitrogen protection for 3 hours; after the reaction is completed, the reaction solution is dispersed with water, extracted twice with ethyl acetate, and the pH of the organic layer is adjusted to neutral with saturated sodium bicarbonate solution, and concentrated under reduced pressure and separated and purified to obtain 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds.

[0030] Example 2: The preparation method of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds is as follows:

[0031] (1) Add 0.1 mmol of the compound of formula II to a container, add 3 mL of formaldehyde to dissolve the compound of formula II, slowly add 0.5 mmol of potassium carbonate under stirring at room temperature, continue stirring at room temperature after the addition is complete, and react overnight; after the reaction is completed, the reaction solution obtained is further separated and purified to obtain the intermediate of the general formula Ш; (2) Add 0.025 mmol of PPA to another container, then add 5 mL of 36.5% concentrated hydrochloric acid, then add 1 mL of anhydrous ethanol, and then add 0.25 mmol of the intermediate of the general formula Ш, and reflux for reaction for 3 hours under nitrogen protection; after the reaction is completed, the reaction solution obtained is further separated and purified to obtain 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds.

[0032] In the above-mentioned embodiment 1-2: when R 1 is hydrogen, R 2 When it is hydrogen, the product obtained is W1 (trans);

[0033] R 1 o-methoxy (o-OCH 3 ), R 2 7,8-dimethoxy(7,8-(OCH 3 ) 2 ), the resulting product is W2 (cis);

[0034] R 1 is para-bromine (p-Br), R 2 is hydrogen, and the products obtained are W3 (cis) and W4 (trans);

[0035] R 1 For p-methoxy (p-OCH 3 ), R 2 is 7-hydroxy (7-OH), and the resulting products are W5 (cis) and W6 (trans);

[0036] R 1 For m-methoxy (m-OCH 3 ), R 2 is 7-hydroxy (7-OH), and the resulting products are W7 (cis) and W8 (trans);

[0037] R 1 is m-dimethoxy (m,m-(OCH 3 ) 2 ), R 2 is 7-hydroxy (7-OH), and the resulting products are W9 (cis) and W10 (trans);

[0038] R 1 is para-fluorine (pF), R 2 is hydrogen, and the products obtained are W11 (cis) and W12 (trans);

[0039] R 1 For m-methoxy (m-OCH 3 ), R 2 7,8-dimethoxy(7,8-(OCH 3 ) 2 ), the resulting product is W13 (cis);

[0040] R 1 is m-dimethoxy (m,m-(OCH 3 ) 2 ), R 2 7,8-dimethoxy(7,8-(OCH 3 ) 2 ), the resulting product is W14 (trans);

[0041] R 1 is para-bromine (p-Br), R 2 is 7-hydroxy (7-OH), and the resulting product is W15 (trans);

[0042] R 1 is o-bromine (o-Br), R 2 is hydrogen, and the obtained product is W16 (trans);

[0043] R 1 o-methoxy (o-OCH 3 ), R 2 is 7-hydroxy (7-OH), and the resulting product is W17 (trans);

[0044] R 1 is o-fluorine (oF), R 2 is hydrogen, and the obtained product is W18 (cis).

[0045] In the preparation method of the present invention, the compound of general formula II includes cis-trans structures when fed, and a mixture of cis-trans isomers is obtained after the reaction. The two have slightly different polarities and can be separated and purified by silica gel column chromatography to obtain the two.

[0046] In order to further confirm the rationality of the preparation method of the present invention and the accuracy of the structure of the synthesized compound, the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds W1-W18 prepared in Example 1-2 were subjected to nuclear magnetic resonance ( 1 H NMR and 13C NMR) detection, the results are as follows:

[0047] W1 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H :7.38(1H,d,J=7.6Hz,H-6),7.32(1H,t,J=7.2Hz,H-7),7.27(1H,s,H-3′),7.27(1H,s,H-5′),7.25~7.21(1H ,s,H-2′),7.27(1H,s,H-6′),7.17(1H,t,J=6.4Hz,H-4′),7.11(1H,t,J=5.6Hz,H-8),6.96(1H,d,J=7.6Hz,H- 9),5.04(2H,d,J=17.6Hz,H-5),4.34(2H,d,J=17.6Hz,H-5),4.11~4.06(1H,m,H-10a),3.94~3.90(1H,m,H-1) ,2.84(2H,dd,J=8.4Hz,10.0Hz,H-2),2.36(2H,t,J=15.6Hz,H-10),2.25(2H,dd,J=4.0,16.0Hz,H-10); EI-MS m / z:263[M] + .

[0048] W2 NMR ( 1 H NMR and 13 C NMR) detection data: light green solid; name: cis-1-(2′-methoxy)-7,8-dimethoxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:7.32(1H,t,J=7.6Hz,H-4′),7.21(1H,d,J=7.2Hz,H-3′),6.99(1H,t,J=7.6Hz,H-5′),6.93(1H,d,J=8. 0Hz,H-6′),6.60(1H,s,H-6),6.43(1H,s,H-9),5.01(1H,d,J=16.8Hz,H-5),4.19~4.15(1H,d,J=10.4Hz, H-5),4.26~4.25(1H,m,H-1),4.23~4.19(1H,m,H-10a),2.87(1H,dd,J=9.6,16.4Hz,H-2),2.69(1H,dd,J =8.8,16.8Hz,H-2),2.27(1H,t,J=15.2Hz,H-10),2.04(1H,dd,J=3.6,15.2Hz,H-10),3.85(3H,s,2′-OCH 3 ),3.84(3H,s,8-OCH 3 ),3.76(3H,s,7-OCH 3 ); 13 C-NMR (CDCl 3 ,100MHz)δc:35.1(C-1),33.6(C-2),173.2(C-3),42.2(C-5),126.2(C-5a),108.8(C-6),147.5(C-7),147.8(C-8),111.9(C-9),123.9 (C-9a),30.1(C-10),56.6(C-10a),125.5(C-1′),157.7(C-2′),127.5(C-3′),128.3(C-4′),120.5(C-5′),110.1(C-6′),55.9(2′-OCH 3 ),55.8(7-OCH 3 ),55.3(8-OCH 3 ); EI-MS m / z(%):353[M] + .

[0049] W3 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: cis-1-(4′-bromo)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:7.53(1H,d,J=8.4Hz,H-3′),7.53(1H,d,J=8.4Hz,H-5′),7.05(1H,d,J=2.4Hz,H-2′),7.05(1H,d,J=2. 4Hz,H-6′),7.34(1H,d,J=6.4Hz,H-6),7.20(1H,d,J=4.4Hz,H-7),7.19~7.18(1H,m,H-8),7.17(1H,d,J =12.4Hz,H-9),4.24(1H,d,J=4.0Hz,H-5),4.21(1H,d,J=4.0Hz,H-5),3.90~3.84(1H,m,H-10a),3.49(1 H,s,H-1),2.73(2H,dd,J=2.0,8.0Hz,H-2),2.60(1H,dd,J=3.2,13.6Hz,H-10),2.22~2.17(1H,m,H-10); 13 C-NMR (CDCl 3 ,100MHz)δc:36.2(C-1),43.3(C-2),176.4(C-3),43.3(C-5),133.9(C-5a),128.7(C-6),128.5(C-7),129.9(C-8),131.2(C-9),13 5.3(C-9a),35.0(C-10),56.8(C-10a),137.5(C-1′),131.8(C-2′),129.6(C-3′),127.9(C-4′),129.6(C-5′),131.8(C-6′); EI-MS m / z:341[M] + .

[0050] W4 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(4′-bromo)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H:7.44(1H,d,J=8.4Hz,H-3′),7.15~7.06(1H,m,H-5′),7.35(1H,d,J=6.7Hz,H-6),7.23~7.21(1H,m,H-7),7.22~ 7.21(1H,m,H-8),7.20(1H,d,J=1.1Hz,H-9),7.08(1H,d,J=6.1Hz,H-2′),7.08(1H,d,J=6.1Hz,H-6′),4.03(1H, d,J=4.9Hz,H-5),4.00(1H,d,J=4.9Hz,H-5),3.30~3.29(1H,m,H-10a),3.17~3.16(1H,m,H-1),3.10~3.09(1H,m ,H-2),2.89(1H,dd,J=8.8,18.6Hz,H-2),2.81(1H,dd,J=9.2,17.4Hz,H-10),2.46(1H,dd,J=8.1,17.3Hz,H-10); 13 C-NMR (CDCl 3 ,125MHz)δc:39.0(C-1),45.7(C-2),176.5(C-3),45.7(C-5),133.9(C-5a),128.5(C-6),127.0(C-7),129.7(C-8),131.1(C-9),13 4.6(C-9a),38.8(C-10),61.2(C-10a),140.3(C-1′),131.8(C-2′),128.6(C-3′),120.8(C-4′),128.6(C-5′),131.8(C-6′); EI-MS m / z:281[M] + .

[0051] W5 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: cis-1-(4′-methoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:7.35(1H,s,H-5′),7.16(1H,d,J=8.8Hz,H-2′),6.91(1H,s,H-6),6.93(1H,s,H-9),6.93(1H,s,H-9a),6.6 3(1H,s,H-4′),6.62(1H,d,J=8.8Hz,H-6′),6.61(1H,s,H-8),4.90(1H,d,J=17.2Hz,H-5),4.25(1H,d,J=17 .2Hz,H-5),4.06~4.00(1H,m,H-10a),3.70~3.61(1H,m,H-1),2.84(1H,dd,J=8.2,13.2Hz,H-2),2.76(1H,d d,J=8.2,13.2Hz,H-2),2.26(1H,t,J=12.0Hz,H-10),2.16(1H,dd,J=4.0,16.0Hz,H-10),3.83(1H,s,3′-OCH 3 ); 13 C-NMR (CDCl 3 ,100MHz)δc:35.5(C-1),39.7(C-2),174.3(C-3),42.5(C-5),130.0(C-5a),113.8(C-6),155.3(C-7),114.0(C-8),128.6(C-9),128.6 (C-9a),30.3(C-10),58.5(C-10a),132.0(C-1′),113.8(C-2′),158.5(C-3′),112.2(C-4′),129.9(C-5′),123.9(C-6′),54.9(3′-OCH 3 ); EI-MS m / z(%):309[M] + .

[0052] NMR of W6 ( 1 H NMR and 13 C NMR) detection data: light yellow solid; name: trans-1-(4′-methoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:7.25(1H,t,J=4.8Hz,H-5′),7.20(1H,s,H-2′),7.14(1H,d,J=8.8Hz,H-9),6.91(1H,s,H-6),6.80(1H,d,J=9 .2Hz,H-6′),6.69(1H,d,J=6.4Hz,H-4′),6.64(1H,d,J=6.4Hz,H-8),4.82(1H,d,J=17.6Hz,H-5),4.32(1H,d, J=17.6Hz,H-5),3.71~3.67(1H,m,H-10a),3.23~3.17(1H,m,H-1),2.76(1H,dd,J=8.8,17.2Hz,H-2),2.84(1H ,dd,J=8.8,17.2Hz,H-2),2.26(1H,t,J=12.0Hz,H-10),2.16(1H,dd,J=4.0,15.2Hz,H-10),3.81(3H,s,3′-OCH 3 ); EI-MS m / z:309[M] + .

[0053] W7 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: cis-1-(3′-methoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H :7.31(1H,t,J=8.0Hz,H-5′),6.87(1H,s,H-2′),6.85(1H,s,H-9),6.83(1H,s,H-6),6.81(1H,s ,H-6′),6.78(1H,s,H-4′),6.62(1H,d,J=7.6Hz,H-8),4.91(1H,d,J=17.2Hz,H-5),4.26(1H,d, J=17.2Hz,H-5),3.92~3.88(1H,m,H-10a),3.40~3.37(1H,m,H-1),2.83(1H,d,J=4.0Hz,H-2),2 .81(1H,d,J=4.0Hz,H-2),2.34~2.27(1H,m,H-10),2.22~2.18(1H,m,H-10),3.84(3H,s,3′-OCH 3 ); 13 C-NMR (CDCl 3,100MHz)δc:35.2(C-1),40.5(C-2),174.1(C-3),42.6(C-5),132.0(C-5a),112.2(C-6),155.3(C-7),113.9(C-8),129.5(C-9),123.9 (C-9a),30.2(C-10),58.3(C-10a),139.5(C-1′),114.1(C-2′),159.5(C-3′),111.9(C-4′),130.1(C-5′),119.9(C-6′),54.9(3′-OCH 3 ); EI-MS m / z:309[M] + .

[0054] W8 NMR ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(3′-methoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H :7.27(1H,t,J=8.9Hz,H-5′),6.92(1H,s,H-2′),6.87(1H,d,J=7.6Hz,H-9),6.83(1H,s,H-6) ,6.82(1H,s,H-6′),6.69(1H,s,H-4′),6.66(1H,s,H-8),4.84(1H,d,J=17.7Hz,H-5),4.33(1H ,d,J=17.7Hz,H-5),3.76~3.72(1H,m,H-10a),3.25~3.19(1H,m,H-1),2.97~2.93(1H,m,H-2) ,2.91~2.88(1H,m,H-2),2.73~2.69(1H,m,H-10),2.67~2.64(1H,m,H-10),3.81(3H,s,3′-OCH 3 ); 13 C-NMR (CDCl 3,125MHz)δc:39.1(C-1),43.0(C-2),173.6(C-3),46.4(C-5),132.2(C-5a),113.1(C-6),155.3(C-7),113.4(C-8),129.9(C-9),124.0 (C-9a),35.1(C-10),61.9(C-10a),142.4(C-1′),114.5(C-2′),159.9(C-3′),112.3(C-4′),130.0(C-5′),119.5(C-6′),55.3(3′-OCH 3 ); EI-MS m / z:309[M] + .

[0055] W9 NMR ( 1 H NMR and 13 C NMR) detection data: light yellow solid; name: cis-1-(3′,5′-dimethoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H :6.97(1H,d,J=6.6Hz,H-9),6.69(1H,s,H-6),6.67(1H,d,J=5.3Hz,H-8),6.43(1H,s,H-2′),6.4 3(1H,s,H-6′),6.39(1H,s,H-4′),4.81(1H,d,J=14.0Hz,H-5),4.32(1H,d,J=13.9Hz,H-5),3.77 ~3.72(1H,m,H-10a),3.18(1H,d,J=9.4Hz,H-1),2.98(1H,dd,J=3.7,15.2Hz,H-2),2.88(1H,dd, J=9.2,36.8Hz,H-2),2.72~2.68(1H,m,H-10),2.66~2.63(1H,m,H-10),3.81~3.78(3H,m,3′-OCH 3 ),3.81~3.78(3H,s,5′-OCH 3 ); EI-MS m / z:339[M] + .

[0056] W10 NMR ( 1 H NMR and 13 C NMR) detection data: light yellow solid; name: trans-1-(3′,5′-dimethoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1H-NMR (CDCl 3 ,400MHz)δ H :6.81(1H,d,J=6.5Hz,H-9),6.41(1H,d,J=1.6Hz,H-8),6.41(1H,s,H-6),6.63(1H,s,H -2′),6.63(1H,s,H-6′),6.37(1H,s,H-4′),4.91(1H,d,J=13.9Hz,H-5),4.23(1H,d,J= 13.6Hz,H-5),4.06~4.01(1H,m,H-10a),2.99(1H,m,H-1),2.80~2.79(1H,m,H-2),2.79 ~2.78(1H,m,H-2),2.35~2.29(1H,m,H-10),2.25~2.21(1H,m,H-10),3.80(3H,s,3′-OCH 3 ),3.80(3H,s,5′-OCH 3 ); 13 C-NMR (CDCl 3 ,100MHz)δc:35.1(C-1),40.8(C-2),174.0(C-3),42.7(C-5),132.3(C-5a),112.4(C-6),155.4(C-7),114.2(C-8),130.3(C-9),124. 1(C-9a),30.2(C-10),58.3(C-10a),140.4(C-1′),106.2(C-2′),160.8(C-3′),98.5(C-4′),160.8(C-5′),106.2(C-6′),55.2(5′-OCH 3 ),55.2(3′-OCH 3 ); EI-MS m / z:339[M] + .

[0057] NMR of W11 ( 1 H NMR and 13 C NMR) detection data: white solid; name: cis-1-(4′-fluoro)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H:7.37(1H,d,J=7.7Hz,H-6),7.31(1H,d,J=7.7Hz,H-7),7.23~7.21(1H,m,H-2′),7.23~7.21(1H,m,H-6′),7.2 1(1H,t,J=8.8Hz,H-8),7.20(1H,d,J=8.3Hz,H-9),7.15~7.06(1H,m,H-3′),7.15~7.06(1H,m,H-5′),5.02(1H, d,J=17.3Hz,H-5),4.32(1H,d,J=17.5Hz,H-5),4.04~4.02(1H,m,H-10a),3.99~3.88(1H,m,H-1),2.87(1H,dd, J=8.8,16.7Hz,H-2),2.75(1H,dd,J=7.9,16.8Hz,H-2),2.63~2.54(1H,m,H-10),2.13(1H,t,J=12.2Hz,H-10); 13 C-NMR (CDCl 3 ,125MHz)δc:35.5(C-1),40.4(C-2),173.3(C-3),42.5(C-5),133.3(C-5a),129.0(C-6),124.9(C-7),128.9(C-8),131.3(C-9),13 3.9(C-9a),28.5(C-10),56.9(C-10a),134.7(C-1′),129.2(C-2′),127.5(C-3′),136.6(C-4′),127.5(C-5′),129.2(C-6′); EI-MS m / z:281[M] + .

[0058] NMR of W12 ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(4′-fluoro)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H:7.33~7.32(1H,m,H-6),7.29(1H,t,J=2.5Hz,H-7),7.28~7.27(1H,m,H-2′),7.28~7.27(1H,m,H-6′ ),7.20~7.19(1H,m,H-8),7.19~7.18(1H,m,H-9),7.15(1H,d,J=1.9Hz,H-3′),7.15(1H,d,J=1.9Hz, H-5′),6.18(1H,s,H-5),3.99~3.97(1H,m,H-10a),3.46(1H,s,J=17.5Hz,H-5),3.31~3.28(1H,m,H- 1),2.87~2.82(1H,m,H-2),2.77~2.61(1H,m,H-2),2.48~2.43(1H,m,H-10),2.22~2.20(1H,m,H-10); 13 C-NMR (CDCl 3 ,125MHz)δc:45.9(C-1),39.1(C-2),175.9(C-3),39.1(C-5),132.8(C-5a),128.9(C-6),127.1(C-7),128.5(C-8),131.1(C-9),13 4.0(C-9a),38.9(C-10),61.1(C-10a),134.7(C-1′),129.8(C-2′),129.8(C-6′),128.4(C-3′),139.9(C-4′),128.4(C-5′); EI-MS m / z:281[M] + .

[0059] NMR of W13 ( 1 H NMR and 13 C NMR) detection data: light green solid; name: cis-1-(3′-methoxy)-7,8-dimethoxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H:7.29(1H,t,J=7.5Hz,H-5′),6.89(1H,d,J=7.5Hz,H-2′),6.84(1H,s,H-4′),6.84(1H,s,H -6′),6.63(1H,s,H-6),6.56(1H,s,H-7),4.85(1H,d,J=17.1Hz,H-5),4.32(1H,d,J=17.1Hz ,H-5),3.93~3.87(1H,m,H-10a),3.23(1H,dd,J=9.3,16.4Hz,H-1),2.99~2.94(1H,m,H-2), 2.92~2.87(1H,m,H-2),2.75~2.72(1H,m,H-10),2.70~2.67(1H,m,H-10),3.86(3H,s,9-OCH 3 ),3.82(3H,s,3′-OCH 3 ),3.82(3H,s,8-OCH 3 ); 13 C-NMR (CDCl 3 ,125MHz)δc:39.1(C-1),42.6(C-2),173.1(C-3),46.4(C-5),124.6(C-5a),113.4(C-6),109.1(C-7),147.7(C-8),148.0(C-9),123. 1(C-9a),35.0(C-10),61.5(C-10a),142.6(C-1′),112.3(C-2′),159.9(C-3′),111.4(C-4′),130.2(C-5′),119.6(C-6′),56.3(9-OCH 3 ),56.2(8-OCH 3 ),56.1(3′-OCH 3 ); EI-MS m / z:353[M] + .

[0060] NMR of W14 ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(3′,5′-dimethoxy)-7,8-dimethoxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:6.66(1H,s,H-9),6.63(1H,s,H-6),6.64(1H,s,H-2′),6.64(1H,s,H-6′),6.2 7(1H,s,H-4′),4.84(1H,d,J=13.7Hz,H-5),4.82(1H,d,J=13.7Hz,H-5),4.14~4 .10(1H,m,H-10a),3.77~3.73(1H,m,H-1),2.99~2.97(1H,m,H-2),2.90~2.88(1 H,m,H-2),2.87~2.84(1H,m,H-10),2.70~2.68(1H,m,H-10),3.80(3H,s,3′-OCH 3 ),3.80(3H,s,5′-OCH 3 ),3.80(3H,s,8-OCH 3 ),3.80(3H,s,7-OCH 3 ); 13 C-NMR (CDCl 3 ,100MHz)δc:39.0(C-1),42.6(C-2),173.5(C-3),46.6(C-5),131.8(C-5a),105.6(C-6),145.8(C-7),148.0(C-8),111.4(C-9),127. 0(C-9a),35.5(C-10),61.3(C-10a),140.4(C-1′),105.4(C-2′),161.1(C-3′),98.6(C-4′),161.1(C-5′),105.4(C-6′),55.0(3′-OCH 3 ),55.0(5′-OCH 3 ),55.3(7-OCH 3 ),55.3(8-OCH 3 ); EI-MS m / z:383[M] + .

[0061] NMR of W15 ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(4′-bromo)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H:7.50(1H,d,J=1.6Hz,H-3′),7.47(1H,d,J=7.5Hz,H-5′),7.19(1H,d,J=1.5Hz,H-2′),7. 17(1H,d,J=1.4Hz,H-6′),6.92(1H,d,J=6.72Hz,H-9),6.67(1H,d,J=6.7Hz,H-6),6.64(1H ,d,J=1.9Hz,H-8),4.80(1H,d,J=14.0Hz,H-5),4.34(1H,d,J=14.0Hz,H-5),3.73~3.69(1H ,m,H-10a),3.26~3.21(1H,m,H-1),2.95~2.87(2H,m,H-2),2.72~2.62(2H,m,H-10); EI-MS m / z:357[M] + .

[0062] NMR of W16 ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(2′-bromo)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,500MHz)δ H :7.59(1H,d,J=8.1Hz,H-3′),7.36~7.35(1H,m,H-6),7.34~7.33(1H,m,H-7),7.33~7.31(1H,m,H-5′),7.3 1~7.30(1H,m,H-8),7.20(1H,d,J=1.9Hz,H-6′),7.19~7.18(1H,m,H-9),7.13(1H,d,J=0.9Hz,H-4′),4.06~ 4.01(1H,m,H-5),3.93~3.89(1H,m,H-5),3.35~3.30(1H,m,H-10a),3.25~3.24(1H,m,H-1),2.96(1H,dd,J =3.8,9.0Hz,H-2),2.89(1H,d,J=9.2Hz,H-2),2.84~2.78(1H,m,H-10),2.42(1H,dd,J=6.7,17.3Hz,H-10); 13 C-NMR (CDCl 3,125MHz)δc:29.7(C-1),39.6(C-2),176.0(C-3),44.8(C-5),131.1(C-5a),128.0(C-6),127.4(C-7),128.5(C-8),128.9(C-9),133.2(C -9a),37.3(C-10),60.3(C-10a),135.0(C-1′),127.1(C-2′),134.2(C-3′),129.9(C-4′),128.6(C-5′),131.3(C-6′); EI-MSm / z:341[M] + .

[0063] NMR of W17 ( 1 H NMR and 13 C NMR) detection data: white solid; name: trans-1-(2′-methoxy)-7-hydroxy-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δ H :7.39(1H,d,J=7.6Hz,H-6′),7.18(1H,t,J=7.2Hz,H-5′),7.02(1H,d,J=13.2Hz,H-9),6.91(1H,s,H-6),6.79 (1H,d,J=8.4Hz,H-3′),6.69(1H,t,J=7.2Hz,H-4′),6.65(1H,d,J=8.4Hz,H-8),4.80(1H,d,J=17.2Hz,H-5),4 .32(1H,d,J=17.6Hz,,H-5),4.27~4.16(1H,m,H-10a),3.55~3.49(1H,m,H-1),2.97~2.85(1H,m,H-2),2.74~2 .56(1H,m,H-2),2.23(1H,t,J=11.6Hz,H-10),2.09~2.039(1H,m,H-10),5.68(1H,s,7-OH),3.83(3H,s,2′-OCH 3 ); EI-MS m / z:309[M] + .

[0064] NMR of W18 ( 1 H NMR and 13 C NMR) detection data: white solid; name: cis-1-(2′-fluoro)-pyrrolo[1,2-b]isoquinoline; 1 H-NMR (CDCl 3 ,400MHz)δH :7.35(1H,d,J=1.6Hz,H-3′),7.32(1H,t,J=7.6Hz,H-4′),7.26(1H,d,J=4.8Hz,H-6),7.23(1H,d, J=6.4Hz,H-6′),7.19(1H,t,J=7.2Hz,H-7),7.14(1H,t,J=3.6Hz,H-8),7.09(1H,d,J=5.2Hz,H-9) ,6.98(1H,t,J=8.0Hz,H-5′),5.04(1H,d,J=17.2Hz,H-5),4.34(1H,d,J=17.2Hz,H-5),4.24~4.15 EI-MS m / z:281[M] + .

[0065] The structural formulas of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds W1-W18 are as follows:

[0066]

[0067] Experimental example:

[0068] 1. Screening scheme for the protective activity of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds against NMDA-induced PC12 cell damage:

[0069] Cells in the logarithmic growth phase were taken at 5×10 5 The cells were inoculated at a density of 100 μL / mL in a 96-well plate and incubated in 5% CO 2 After incubation in the incubator for 48 hours, the cells were divided into the control group, model group, and injury-adding drug treatment group, with 5 replicates in each group. The control group and the model group were only added with DMEM culture medium, and the injury-adding drug treatment group was added with 1-phenyl-1,2,10,10a-tetrahydropyrrole [1,2-b] isoquinoline-3 (5H) -one compounds at a concentration of 20μM. Each group was placed in the incubator for 24 hours. After 24 hours, 20mM NMDA was added to the model group and the injury-adding drug treatment group, and the cells were placed in the incubator for 6 hours. After 6 hours, MTT was added and incubated for 4 hours, and the cell survival rate was detected by MTT method. The absorbance value of each group of cells was measured at 490nm using an enzyme marker. The calculation formula is: survival rate = treatment group / normal cell group) × 100%.

[0070] Damage protection results: Figure 1As shown, 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds W1, W8, W9, W10, W11, W12, W15, and W17 have obvious damage-protective activity on cells at a concentration of 20 μM, especially W12, which has extremely obvious protective activity, indicating that it can be used to prepare drugs for neurodegenerative diseases.

[0071] II. Screening scheme for the antidepressant activity of 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds in mice:

[0072] 1. Model and preparation

[0073] All mice were allowed to drink water and eat freely. After one week of adaptation in a quiet environment with a light-dark cycle of 12 h, the chronic mild unpredictable stress animal model (CUMS) was modified by the Willner P method and combined with solitary housing for experiments. The mice receiving stress treatment were randomly exposed to different stimuli within 21 days, one per day, and the same type of stimulation could not appear continuously. The stress operation methods were as follows: tilting the mouse cage (45°, 24 h), water and food deprivation (24 h), ice water swimming (4°C, 5 min), tail clamping (1 min), heat stress (45°C, 5 min), flash stimulation (frequency 3 times / min), wet bedding (24 h), day and night reversal (24 h).

[0074] 2. Grouping and Dosing

[0075] Two days before the experiment, each mouse was subjected to a 1-hour sugar water preference test. According to the results of sugar water preference, mice with no significant difference were selected and weighed. An open-field experiment was performed one day before the experiment. Mice with large differences in the total distance of central activity were eliminated. 60 mice were randomly divided into a blank control group, a model group, and an amitriptyline group (15 mg / kg); W1 low, medium, and high (0.83 mg / kg, 4.16 mg / kg, and 8.33 mg / kg) drug groups, 10 mice in each group, the blank control group and the model group were gavaged with an equal volume of distilled water, and the other groups were continuously administered for 21 days. Except for the blank control group, each mouse in the other groups was kept alone.

[0076] 3. Behavioral Experiment

[0077] 3.1 Forced Swimming Test (FST)

[0078] On the 21st day, 1 hour after gavage, the mice were placed in a forced swimming apparatus (a glass tank with a diameter of 30 cm and a height of 40 cm, filled with 23±1℃ wet water, a water depth of 25 cm, and a camera installed opposite the forced swimming apparatus). Then a computer was used to time the 4-min video and record the cumulative immobility time of the mice in the next 3 minutes.

[0079] 3.2 Open Field Test (OFT)

[0080] The open field box is composed of 4 square boxes with a length, width and height of 40 cm. It can test 4 experimental animals at the same time. The bottom of each box is divided into a central area (50% of the open box bottom area) and a peripheral area (50% of the open box bottom area) by software settings. The environment was kept relatively quiet during the experiment. At the beginning of each experiment, the experimental box was wiped with 75% ethanol to eliminate interfering odors. After the ethanol was completely evaporated, the mouse was placed in a fixed corner with its head facing up and its body against the box wall. It was allowed to move autonomously for 4 minutes and the total distance (mm) in the last 3 minutes was recorded.

[0081] 3.3 Tail Suspension Test (TST)

[0082] When the mouse's tail was hung up so that its entire body was suspended in the air, the computer was used to record the 4-minute video and the mouse's immobility time for the next 3 minutes.

[0083] 4. Nissl staining

[0084] Nissl bodies are one of the characteristic structures of neurons. They exist in the cell bodies and dendrites of neurons. They are basophilic and can be stained blue-purple by alkaline dyes such as toluidine blue. When neurons are stimulated, the number of Nissl bodies in the cell bodies will be significantly reduced. The number and color depth of Nissl bodies are positively correlated with the functional state of neurons. The experimental steps are as follows: the right hemisphere of the brain tissue is placed in a 4% paraformaldehyde solution for 48 hours, dehydrated with gradient alcohol, transparentized with xylene, and embedded into paraffin blocks. The wax block containing the tissue is cut into 5μm thick paraffin sections, the slide is scooped out, the slices are placed in a 60℃ oven for 50 minutes, cooled to room temperature, and placed in a slice box at 4℃ for storage for later use. Dewaxing: xylene I 10min → xylene II 10min; hydration: anhydrous ethanol 5min → 95% ethanol 5min → 80% ethanol 5min → double distilled water washing 1min×2 times; gently wipe the liquid around the tissue dry, add the toluidine blue staining solution that has just been filtered (0.22μm pore size needle filter) to the tissue with a pipette (about 200μL / sheet), place in a humidified box at 60℃ for 45min → double distilled water washing 3min×3 times → anhydrous ethanol dehydration 2s, evaporate and seal with neutral plastic containing xylene and make transparent. Observe the surviving neurons in the cortex and hippocampal CA2 region under an inverted optical microscope, and observe the hippocampal neurons under 200× magnification.

[0085] 5. Statistical processing

[0086] SPSS17.0 statistical software was used to process the data, and the measurement data were expressed as ±s. One-way ANOVA was used to examine the significance of the differences between the groups.

[0087] 6. Test results

[0088] Antidepressant activity and Nissl staining results in mice:

[0089] Figure 2 The results of forced swimming immobility time showed that compared with the blank group, the immobility time of the model group in the forced swimming test was significantly increased (P < 0.001); compared with the model group, the immobility time of the W1-administered group in the forced swimming test was significantly decreased (P < 0.001).

[0090] Figure 3 The statistical results of the tail suspension test and immobility test showed that compared with the blank group, the immobility time of the mice in the model group in the tail suspension test was significantly increased (P < 0.001); compared with the model group, the immobility time of the W1-treated group in the tail suspension test was significantly decreased (P < 0.001).

[0091] Figure 4 The results of the open field test showed that compared with the blank group, the total distance traveled by the mice in the model group was reduced (P < 0.05); compared with the model group, the total distance traveled by the high-dose W1 group was significantly increased (P < 0.05).

[0092] Figure 5 The results of the effect of W1 on the hippocampal neurons of anxious mice induced by chronic stress (Nissl staining) showed that the Nissl-stained hippocampal neurons of the blank group mice were granular, tightly and neatly arranged, with a small number of apoptotic neurons; the Nissl-stained hippocampal neurons of the model group mice were sparsely dispersed and arranged in a disorderly manner, with a large number of apoptotic neurons and a significantly reduced number of surviving cells; the hippocampal neurons of the positive drug and W1 dose groups were still neatly arranged, but the intercellular gaps were widened, and the number of apoptotic neurons was small, indicating that W1 has a protective effect on hippocampal neurons.

[0093] 3. Conclusion:

[0094] The NMDA-induced PC12 cell damage protection experiment proved that 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds W1, W8, W9, W10, W11, W12, W15, and W17 had obvious damage protection activity on cells at a concentration of 20 μM, especially W12, which had extremely obvious protective activity, indicating that it can be used to prepare drugs for neurodegenerative diseases.

[0095] In vitro antidepressant activity studies in mice found that 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound W1 has significant antidepressant effects.

[0096] Nissl staining revealed that W1 had a protective effect on mouse hippocampal neurons, suggesting that 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compounds can be used in the preparation of antidepressant drugs.

Claims

1. A 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compound, Features: The structural formula of the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound is as shown in general formula I: The specific compound is any one of the following W1-W18:

2. The method for preparing 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds as claimed in claim 1, It is characterized in that The steps are as follows: (1) dissolving the compound represented by the general formula II with formaldehyde, adding potassium carbonate and stirring the reaction at room temperature to obtain the intermediate represented by the general formula Ш; (2) sequentially adding PPA, 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш, and reflux reaction under nitrogen protection to obtain 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound Ⅰ; the reaction route is as follows:

3. The method for preparing 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds according to claim 2, Features: In step (1), the compound represented by general formula II is dissolved in formaldehyde, and potassium carbonate is slowly added under stirring at room temperature. After the addition is completed, stirring is continued at room temperature to react overnight. After the reaction is completed, the reaction solution is dispersed with water, extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure and then separated and purified to obtain the intermediate represented by general formula Ш.

4. The method for preparing 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds according to claim 2 or 3, Features: In step (1), the compound represented by general formula II, formaldehyde and potassium carbonate are added in a ratio of 0.1 mmol: 3 mL: 0.5 mmol.

5. The method for preparing 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds according to claim 2, Features: In step (2), PPA, 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш are added in sequence, and the reaction is refluxed for 3 hours under nitrogen protection. After the reaction is completed, the reaction solution is dispersed with water, extracted twice with ethyl acetate, and the pH of the organic layer is adjusted to 7.0 with saturated sodium bicarbonate solution. The reaction mixture is concentrated under reduced pressure and then separated and purified to obtain 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound I.

6. The method for preparing 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinolin-3(5H)-one compounds according to claim 2 or 5, Features: In step (2), PPA, 36.5% concentrated hydrochloric acid, anhydrous ethanol and the intermediate represented by the general formula Ш are added in a ratio of 0.01 mmol: 2 mL: 0.4 mL: 0.1 mmol.

7. Use of the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound as claimed in claim 1 in the preparation of drugs for treating neurodegenerative diseases.

8. Use of the 1-phenyl-1,2,10,10a-tetrahydropyrrolo[1,2-b]isoquinoline-3(5H)-one compound W1 as claimed in claim 1 in the preparation of a drug for treating depression.

Images