CN108997308A - A kind of benzimidazoles derivative and its preparation method and application - Google Patents

Abstract

The invention discloses a kind of benzimidazoles derivatives and its preparation method and application, it can be effectively reduced the relapse rate after morphine addiction is given up by benzimidazoles derivative prepared by the application, for inhibiting precipitated morphine withdrawal that there is significant effect, there is wide applicability in technical field in the drug of preparation prevention and/or treatment dependence producing drug habituation, there is biggish Development volue in the technical field of pharmaceuticals relapsed after preparation prevention and/or treatment dependence producing drug are given up.

Description

A kind of benzimidazole derivative and its preparation method and application

technical field

The present invention mainly relates to the technical field of pharmaceutical chemical preparation, in particular, the present invention relates to the technical field of benzimidazole derivatives and their preparation methods and applications.

Background technique

Drug addiction is a chronic recurrent brain disease characterized by compulsive drug use and loss of control. Relapse is a difficult part of detoxification treatment. The international anti-drug convention divides the drugs of dependence into three categories: narcotic drugs, psychotropic drugs and others. Among them, narcotic drugs are divided into opioids, cocaine, cannabis, etc.; psychotropic drugs are divided into sedative hypnotics and anxiolytics such as barbiturates, central stimulants such as amphetamines, hallucinogens such as ergot diethylamine, etc.; It also includes alcohol, tobacco and volatile organic solvents. Drug addiction has become a worldwide public health and social problem, seriously endangering human health and affecting social stability and harmonious development. Existing detoxification treatment for drug dependence has accumulated a lot of experience, physical withdrawal symptoms can be controlled through detoxification treatment, but it is still difficult to control relapse caused by psychological craving caused by drug withdrawal, which is the current domestic and foreign drug detoxification method. Difficulties in treatment.

A lot of research on benzimidazole derivatives has been disclosed at home and abroad, and one patent application number is 2016102193169, which discloses a "substituted benzimidazole derivative", which can selectively inhibit CDK4/ 6. It has a good inhibitory effect on cell proliferation, and can be used for various diseases caused by the disorder of cell cycle control involving CDK4/6, especially for the treatment of malignant tumors; the patent application number 201710991758X discloses a "a benzo The preparation method of imidazole derivatives and their application in anti-tumor", said benzimidazole derivatives can significantly inhibit the activity of topoisomerase II and effectively inhibit the proliferation of tumor cells; the patent application number is 2016800423588 Provides a "benzimidazole derivative as a PAD4 inhibitor", which can be used for the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis , asthma, lupus erythematosus and psoriasis.

At present, the benzimidazole derivatives disclosed in journals and patent documents are mainly used in various diseases such as tumors, and no benzimidazole derivatives that can be used to resist drug addiction have been disclosed or researched. The commonly used treatment method for psychological craving after drug dependence withdrawal is substitution therapy. The psychological craving is still difficult to eliminate and can only be taken for life. At present, there is an extreme lack of effective anti-drug addiction compounds. Therefore, the research and development of effective drug addiction psychological The desired compound is imminent.

Contents of the invention

Aiming at the current technical status of benzimidazole derivatives used for anti-drug addiction, which is difficult to eliminate after drug dependence and withdrawal, the present invention aims to provide a kind of benzimidazole derivatives and its preparation Method and application, the benzimidazole derivatives prepared by this application can effectively reduce the relapse rate after morphine addiction withdrawal, have a significant effect on suppressing morphine withdrawal symptoms, and have a wide range of practical applications in the technical field of pharmaceutical preparation sex and development value.

In order to realize the purpose of the present invention, the technical scheme that the present invention takes is as follows:

The present invention specifically provides a benzimidazole derivative represented by general formula (I):

Preferably, in general formula (I), R ₁ =H.

Preferably, in general formula (I), R ₂ =H or O.

Preferably, in the general formula (I), X═C or N or O or S.

Preferably, in the general formula (I), n=0 or 1.

Preferably, in the general formula (I), R ₁ is any one of an alkyl substituent, a phenyl substituent, and a benzyl substituent.

Preferably, in the general formula (I), R ₂ is any one of an alkyl substituent, a phenyl substituent, a benzyl substituent, and an acyl substituent.

More preferably, representative compounds in the general formula (I) of the present invention are as follows:

Simultaneously, the present invention provides the preparation method of above-mentioned benzimidazole derivatives, specifically adopt the following technical steps:

At the same time, the present invention provides the application of the above-mentioned benzimidazole derivatives in the preparation of drugs for preventing and/or treating addiction.

At the same time, the present invention provides the application of the above-mentioned benzimidazole derivatives in the preparation of drugs for preventing and/or treating relapse after withdrawal of addictive drugs.

Preferably, the addictive drug refers to any one or two or more of narcotic drugs or psychotropic drugs or alcohol, tobacco, and volatile organic solvents.

Preferably, the narcotic drugs include opioids, cocaine, and marijuana, and the opioids include opium from natural sources and the active ingredient morphine extracted therefrom, as well as heroin, a product obtained by processing the active ingredients, and synthetic products similar to opioids.

By implementing the technical scheme of the present invention, the following beneficial effects can be achieved:

(1) Aiming at the current technical situation of benzimidazole derivatives used for anti-drug addiction that is difficult to eliminate after drug dependence and withdrawal, the present invention provides a kind of benzimidazole derivatives and its The preparation method and application, the benzimidazole derivatives prepared by this application can effectively reduce the relapse rate after morphine addiction withdrawal, have a significant effect on suppressing morphine withdrawal symptoms, and have a wide range of applications in the field of pharmaceutical preparation technology Practicality and development value.

(2) After administering the benzimidazole derivative TUP-14 prepared by the present invention to experimental rats by intragastric administration, it was found that the rats not given benzimidazole derivatives had conditioned place preference and sensitization, and X benzene was administered. After treatment with imidazole derivatives, the formation of conditioned place preference and sensitization was inhibited, indicating that benzimidazole derivatives can inhibit the formation of morphine addiction; at the same time, after treatment with benzimidazole derivatives, the formation of conditioned place preference and sensitization was inhibited Formation of relapse after withdrawal indicates that the benzimidazole derivatives provided by the invention can inhibit relapse after withdrawal of morphine addiction.

(3) The benzimidazole derivative TUP-14 prepared by the present invention is used as a drug for anti-morphine and cocaine addiction high-incidence activities, and by establishing morphine and cocaine-sensitized rat models, it can be known that morphine or cocaine-TUP-14 Group rat spontaneous activity is obviously lower than not giving benzimidazole derivatives TUP-14 experimental group, excitability obviously reduces, illustrates that benzimidazole derivatives TUP-14 provided by the present invention has a certain effect on the formation of morphine or cocaine sensitization. Certain inhibitory effect.

(4) Using the benzimidazole derivative TUP-14 prepared by the present invention as a drug against psychological craving for morphine addiction, a morphine conditioned place preference (conditioned place preference, CPP) model was established, and the conditioned place preference of rats in the normal saline control group was found Preference still exists; while in the benzimidazole derivatives TUP-14 administration group, the CPP Score decreased significantly, and the difference between the administration group and the control group was significant, indicating that the benzimidazole derivatives TUP-14 provided by the present invention Can improve the symptoms of morphine addiction.

Description of drawings

Figure 1 shows a diagram of the spontaneous activity box setup.

Figure 2 shows the effect of TUP-14 on sensitization to morphine and cocaine.

Figure 3 shows a diagram of the conditional place preference device.

Fig. 4 is a flowchart of the administration experiment, wherein A is a flowchart of the administration experiment of TUP-14.

Detailed ways

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to the following examples.

The reagents and materials used in the present invention can be purchased through public channels, and the equipment and instruments used in the process are all common equipment in the art.

All materials, reagents and instruments selected in the present invention are well known in the art, but do not limit the implementation of the present invention, and some other reagents and equipment well known in the art are applicable to the implementation of the following embodiments of the present invention.

Embodiment 1: A kind of benzimidazole derivative

The present invention specifically provides a benzimidazole derivative represented by general formula (I):

Preferably, in general formula (I), R ₁ =H.

Preferably, in general formula (I), R ₂ =H or O.

Preferably, in the general formula (I), X═C or N or O or S.

Preferably, in the general formula (I), n=0 or 1.

Preferably, in the general formula (I), R ₁ is any one of an alkyl substituent, a phenyl substituent, and a benzyl substituent.

Preferably, in the general formula (I), R ₂ is any one of an alkyl substituent, a phenyl substituent, a benzyl substituent, and an acyl substituent.

Embodiment two: the preparation method of benzimidazole derivatives

Specifically adopt the following steps to prepare benzimidazole derivatives:

Example 3: Preparation and structure identification of benzimidazole derivative TUP-01

Take a 30mL dried microwave tube, add 2-chlorobenzimidazole (0.457g, 3mmol), dissolve in 6mL of methanol, add tetrahydropyrrole (0.32mL, 3.9mmol), and react in microwave at 160°C for 2.5h. Spin to dry the solvent, add 200mL ethyl acetate to dissolve, wash with 200mL water and 200mL saturated brine respectively, and dry the organic phase with anhydrous sodium sulfate. The organic phase was spin-dried to obtain the benzimidazole derivative TUP-01, 0.274 g of white solid, with a yield of 41%. The structural formula of benzimidazole derivative TUP-01 is:

Example 4: Preparation and structure identification of benzimidazole derivative TUP-02

(1) Preparation method:

Take a dried 10mL microwave tube, add 2-chlorobenzimidazole (305mg, 2mmol), dissolve it in 4mL of methanol, then add piperidine (1.09mL, 12mmol), and react in microwave at 160°C for 2.5h. The reaction solution was spin-dried, separated by a chromatographic column, and the mobile phase was PE:EA=2:1. The benzimidazole derivative TUP-02 was obtained, 349 mg of white crystals, with a yield of 88%. The structural formula of benzimidazole derivative TUP-02 is:

(2) Identification results:

mp276-277℃; IR(film): v _max /cm ^-1 : 3336, 3049, 2906, 2850, 1628, 1600, 1571, 1462, 1358, 1308, 1268, 1239, 1136, 1097, 1047, 735; ¹ H NMR (400MHz, CD ₃ OD) δ7.23 (dd, J=5.8, 3.2Hz, 2H), 6.99 (dd, J=5.8, 3.2Hz, 2H), 3.53(s, 4H), 1.70(s, 6H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ 155.1, 136.8, 120.8, 112.1, 47.4, 25.1, 24.0; MS(ES) (m/z) calcd for C ₁₂ H ₁₆ N ₃ 202.1344, found 202.1338.

Example 5: Preparation and structure identification of benzimidazole derivative TUP-03

(1) Preparation method:

Take a dried 10mL microwave tube, add 2-chlorobenzimidazole (305mg, 2mmol), dissolve in 4mL of methanol, then add 2-methylpiperidine (1.41mL, 12mmol), and microwave at 160°C for 2.5h. The reaction solution was spin-dried, separated by a chromatographic column, and the mobile phase was PE:EA=2:1. The benzimidazole derivative TUP-03 was obtained, 374 mg of white solid, with a yield of 88%. The structural formula of benzimidazole derivative TUP-03 is:

(2) Identification results:

mp233-234℃; IR (film): v _max /cm ^-1 :3064, 2929, 2850, 1624, 1557, 1464, 1419, 1286, 1265, 1182, 1143, 1063, 1004, 737; ¹ H NMR (400MHz , CD ₃ OD) δ7.30-7.20 (m, 2H), 7.05-6.98 (m, 2H), 4.43-4.34 (m, 1H), 3.88 (dd, J=12.7, 3.8Hz, 1H), 3.20 ( td, J=12.8, 2.9Hz, 1H), 1.90–1.60 (m, 6H), 1.28 (d, J=6.8Hz, 3H); ¹³ C NMR (101MHz, CD ₃ OD) δ159.9, 141.6, 123.8 , 115.3, 52.6, 44.5, 33.6, 29.0, 22.0, 17.3; MS (ES) (m/z) calcd for C ₁₃ H ₁₈ N ₃ 216.1500, found 216.1493.

Example 6: Preparation and structure identification of benzimidazole derivative TUP-04

(1) Preparation method:

Take a 30mL dried microwave tube, add 2-chlorobenzimidazole (0.457g, 3mmol), dissolve in 6mL of methanol, then add 3-methylpiperidine (0.45mL, 3.9mmol), and microwave at 160°C for 2.5h. Spin to dry the solvent, add 170mL ethyl acetate to dissolve, wash with 200mL water and 200mL saturated brine respectively, and dry the organic phase with anhydrous sodium sulfate. The organic phase was spin-dried to obtain the benzimidazole derivative TUP-04, 0.431 g of white solid, with a yield of 67%. The structural formula of benzimidazole derivative TUP-04 is:

(2) Identification results:

mp189℃; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.18-7.15(t, J=12Hz, 2H), 6.90(s, 2H), 4.03-3.99(t, J=16Hz, 2H) , 2.92-2.85(m, 1H), 2.59-2.53(m, 1H), 1.78-1.48(m, 4H), 1.42-1.09(m, 1H), 0.91-0.90(d, J=4Hz, 3H); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO) δ 156.1, 53.3, 46.2, 32.4, 30.0, 24.3, 19.0.

Example 7: Preparation and structure identification of benzimidazole derivative TUP-05

(1) Preparation method:

Take a 30mL dried microwave tube, add 2-chlorobenzimidazole (0.457g, 3mmol), dissolve in 6mL of methanol, then add 4-methylpiperidine (0.45mL, 3.9mmol), and microwave at 160°C for 2.5h. Spin to dry the solvent, add 150mL ethyl acetate to dissolve, wash with 200mL water and 200mL saturated brine respectively, and dry the organic phase with anhydrous sodium sulfate. The organic phase was spin-dried to obtain the benzimidazole derivative TUP-05, 0.320 g of white solid, and the yield was 50%. The structural formula of benzimidazole derivative TUP-05 is:

(2) Identification results:

mp209-210°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.18-7.15 (m, 2H), 6.91-6.89 (m, 2H), 4.09-4.06 (d, J=12Hz, 2H) , 2.95-2.88(m, 2H), 1.68-1.57(m, 3H), 1.21-1.14(m, 2H), 0.93-0.92(d, J=4Hz, 3H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ 156.2, 119.3, 46.2, 33.0, 30.2, 21.8.

Example 8: Preparation and structure identification of benzimidazole derivative TUP-06

(1) Preparation method:

Take the dried 10mL microwave tube, add 2-chlorobenzimidazole (305mg, 2mmol), dissolve in 4mL methanol, then add 1,2,3,4-tetrahydroquinoline (1.51mL, 12mmol), microwave reaction at 160°C 2.5h. The reaction solution was spin-dried, separated by a chromatographic column, and the mobile phase was PE:EA=2:1. The benzimidazole derivative TUP-06 was obtained, 473 mg of white solid, with a yield of 95%. The structural formula of benzimidazole derivative TUP-06 is:

(2) Identification results:

mp268-270℃; IR (film): v _max /cm ^-1 :3039, 2943, 2750, 1633, 1592, 1540, 1493, 1474, 1364, 1267, 1246, 1184, 1142, 1013, 749; ¹ H NMR (400MHz, CD ₃ OD) δ7.61(d, J=8.0Hz, 1H), 7.50(dt, J=7.1, 3.6Hz, 2H), 7.41(ddd, J=9.3, 7.3, 2.3Hz, 4H) , 7.31(dd, J=10.8, 4.0Hz, 1H), 4.02(t, J=6.5Hz, 2H), 2.89(t, J=6.2Hz, 2H), 2.22-2.12(m, 2H); ¹³ C NMR (101MHz, CD ₃ OD) δ148.9, 135.6, 133.3, 129.7, 129.1, 127.6, 126.2, 124.1, 120.9, 111.5, 26.1, 23.3; MS(ES) (m/z) calcdforC ₁₆ H ₁₆ N ₃ 250.1344 , found 250.1338.

Example 9: Preparation and structure identification of benzimidazole derivative TUP-07

(1) Preparation method:

Take the dried 30mL microwave tube, add 2-chlorobenzimidazole (2.1g, 13.75mmol), 4-hydroxypiperidine (1.28g, 12.5mmol), add methanol 8mL to dissolve, then add N,N-diiso Propylethylamine (DIPEA, 6.5mL, 37.2mmol), microwave reaction at 160°C for 2.5h. The reaction solution was spin-dried, separated by a chromatographic column, and the mobile phase was MeOH:DCM=1:1. The benzimidazole derivative TUP-07 was obtained, 1.6 g of white solid, with a yield of 59%. The structural formula of benzimidazole derivative TUP-07 is:

(2) Identification results:

mp279℃; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.18-7.15 (m, 2H), 6.91-6.89 (m, 2H), 4.78 (s, 1H), 3.90-3.84 (m, 2H) ), 3.72-3.68(m, 1H), 3.19-3.13(m, 2H), 1.83-1.79(m, 2H), 1.44-1.40(m, 2H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO ) δ 156.0, 119.4, 65.7, 43.9, 33.4; MS (ES) (m/z) calcd for C ₁₂ H ₁₆ N ₃ O 218.1293, found 218.1279.

Example 10: Preparation and structure identification of benzimidazole derivative TUP-08

(1) Preparation method:

Take 10mL dried sealed tube, add 2-chlorobenzimidazole (0.366g, 2.4mmol), 4-piperidone ketal (256μL, 2mmol), add methanol 2mL to dissolve, then add DIPEA (1.05mL, 6mmol), the temperature was raised to 140°C for 13h. The reaction solution was spin-dried, separated by a chromatographic column, and the mobile phase was MeOH:DCM=1:30. The benzimidazole derivative TUP-08 was obtained, 0.486 g of white solid, with a yield of 64%. The structural formula of benzimidazole derivative TUP-08 is:

(2) Identification results:

mp301-302°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.20-7.18(m, 2H), 6.94-6.91(m, 2H), 3.92(s, 4H), 3.62-3.60(t , J=12Hz, 4H), 1.72-1.69 (t, J=12Hz, 4H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ155.6, 119.6, 106.3, 63.8, 44.4, 33.8; MS ( ES) (m/z) _calcd for _{C14H18N3O2 260.1399} , found _260.1383 .

Example 11: Preparation and structure identification of benzimidazole derivative TUP-09

(1) Preparation method:

Take the dried 30mL sealed tube, add compound TUP-08 (0.518g, 2mmol), 4mL each of methanol and water, add concentrated hydrochloric acid (2.5mL, 30mmol), heat up to 100°C for 24h. Cool down to 0°C, adjust pH to 10 with 5M sodium hydroxide solution, stir for 30 minutes, spin dry the solvent, extract with 500mL ethyl acetate, wash with 200mL water and 200mL saturated brine respectively, and wash the organic phase with anhydrous sodium sulfate dry. The organic phase was spin-dried to obtain the benzimidazole derivative TUP-09, 0.333 g of white solid, with a yield of 77%. The structural formula of benzimidazole derivative TUP-09 is:

(2) Identification results:

¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.23(s, 2H), 6.95(s, 2H), 3.87(s, 4H), 2.47-2.46(d, J=4Hz, 4H); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO) δ 207.2, 155.1, 45.4; MS (ES) (m/z) calcd for C ₁₂ H ₁₄ N ₃ O 216.1137, found 216.1122.

Example 12: Preparation and structure identification of benzimidazole derivative TUP-10

(1) Preparation method:

In a 100mL round bottom flask, add 2-chlorobenzimidazole (6.1g, 40mmol), piperazine (4.5g, 52mmol), n-butanol 40mL, DIPEA (13.9mL, 160mmol), heat up to 130°C, and react for 18h . The solvent was spin-dried, washed with 300 mL of water, and the filtered solid was washed with 100 mL of ethyl acetate, 10 mL of methanol and 200 mL of methyl tert-butyl ether, and dried in a vacuum oven at 40°C. The benzimidazole derivative TUP-10 was obtained, 4.74 g of white solid, with a yield of 59%. The structural formula of benzimidazole derivative TUP-10 is:

(2) Identification results:

mp259-260°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.26-7.23 (m, 2H), 6.98-6.95 (m, 2H), 3.78-3.76 (t, J=8Hz, 4H) , 3.22-3.19 (t, J=12Hz, 4H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ155.7, 120.4, 43.6, 42.4; MS (ES) (m/z) calcd for C ₁₁ H ₁₅ N ₄ 203.1296, found 203.1285.

Example 13: Preparation and structure identification of benzimidazole derivative TUP-11

(1) Preparation method:

In a 100mL round bottom flask, add 2-chlorobenzimidazole (3.168g, 20.76mmol), 4-tert-butoxycarbonylaminopiperidine (5.405g, 26.98mmol), n-butanol 40mL, DIPEA (14.5mL, 83.04 mmol), the temperature was raised to 130°C, and the reaction was carried out for 18h. The solvent was spin-dried, washed with 500 mL of water, and the solid obtained by filtration was washed with 100 mL of ethyl acetate, 10 mL of methanol and 200 mL of methyl tert-butyl ether, and dried in a vacuum oven at 40°C. The benzimidazole derivative TUP-11 was obtained, 5.698 g of white solid, with a yield of 87%. The structural formula of benzimidazole derivative TUP-11 is:

(2) Identification results:

mp260°C; ¹ H NMR (400MHz, CD ₃ OD) δ7.13-7.11 (m, 2H), 6.90-6.87 (m, 2H), 3.94-3.91 (d, J=12Hz, 2H), 3.52-3.46 ( t, J=24Hz, 1H), 3.07-3.00(m, 2H), 1.86-1.84(d, J=8Hz, 2H), 1.44-1.40(m, 2H), 1.34(s, 9H); ¹³ CNMR( 101 MHz, CD ₃ OD) δ 157.4, 121.6, 80.1, 46.7, 32.5, 28.8; MS (ES) (m/z) calcd for C ₁₇ H ₂₅ N ₄ O ₂ 317.1977, found 317.1962.

Example 14: Preparation and structure identification of benzimidazole derivative TUP-12

(1) Preparation method:

In a 100mL round bottom flask, add benzimidazole derivative TUP-11 (2.86g, 9.04mmol), methanol 30mL, cool down to 0°C, add hydrochloric acid/1,4-dioxane (1:1) 8mL , stirred at room temperature for 24h. The solid was filtered, washed with 200mL of methanol and 200mL of methyl tert-butyl ether respectively, dissolved in 100mL of water, cooled to 0°C, slowly added with 5M sodium hydroxide solution to adjust the pH to 12, a white solid was precipitated, filtered, and then washed with Wash with 200 mL of water and 200 mL of methyl tert-butyl ether, and dry in a vacuum oven at 40°C. The benzimidazole derivative TUP-12 was obtained, 1.362 g of white solid, with a yield of 70%. The structural formula of benzimidazole derivative TUP-12 is:

(2) Identification results:

mp207-208°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.17-7.15 (m, 2H), 6.91-6.88 (m, 2H), 4.03-3.99 (d, J=16Hz, 2H) , 3.03-2.96(m, 2H), 2.81-2.76(m, 1H), 1.79-1.75(m, 2H), 1.28-1.23(m, 2H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ 156.1, 119.4, 111.8, 48.0, 45.0, 34.4; MS (ES) (m/z) calcd for C ₁₂ H ₁₇ N ₄ 217.1453, found 217.1442.

Example 15: Preparation and structure identification of benzimidazole derivative TUP-13

(1) Preparation method:

In a 250mL round bottom flask, add benzimidazole derivatives TUP-12 (2.919g, 13.49mmol), 2-amino-3-methoxybenzoic acid (2.14g, 12.81mmol), HOBT (5.469g, 40.47 mmol), EDCI (3.102g, 16.188mmol), DMF 40mL, stirred at room temperature for 1h, added DIPEA (14.1mL, 80.8mmol), and reacted at room temperature for 15h. Add 1000 mL of water, filter out the solid, wash the solid with 100 mL of water, 100 mL of ethyl acetate, and 200 mL of methyl tert-butyl ether, and dry in a vacuum oven at 40°C. The benzimidazole derivative TUP-13 was obtained, 4.224 g of off-white solid, with a yield of 86%. The structural formula of benzimidazole derivative TUP-13 is:

(2) Identification results:

mp287-288°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ8.06-8.04 (d, J=8Hz, 1H), 7.20-7.14 (m, 3H), 6.93-6.87 (m, 3H) , 6.52-6.48(t, J=16Hz, 1H), 6.10(s, 2H), 4.14-4.05(m, 3H), 3.78(s, 3H), 3.12-3.06(t, J=24Hz, 2H), 1.87-1.84 (d, J=12Hz, 2H), 1.66-1.58 (m, 2H); ¹³ CNMR (101MHz, (CD ₃ ) ₂ SO) δ168.6, 156.4, 147.3140.0, 120.4, 120.0, 115.0, 114.4, 112.3, 56.0, 46.5, 46.0, 31.0; MS (ES) (m/z) _calcd for _{C20H24N5O2 366.1930} , found _366.1912 .

Example 16: Preparation and structure identification of benzimidazole derivative TUP-14

(1) Preparation method:

The 500mL round-bottomed flask was dried, pumped and ventilated three times to fill the bottle with nitrogen, a nitrogen balloon was inserted, a benzimidazole derivative TUP-13 (1.644g, 4.5mmol) was added, and 45mL of redistilled dichloromethane was added. Cool down to -20°C, slowly add 1M dichloromethane boron tribromide solution (45mL, 45mmol), stir at room temperature for 8h, cool down to -20°C, slowly add methanol 90mL to quench the reaction, and stir at room temperature for 10h. Spin to dry the solvent, add 600mL of water and 100mL of ethyl acetate to wash, adjust the pH to 7 with 5M sodium hydroxide solution to precipitate the product, add 600mL of water to wash, and dry in a vacuum oven at 40°C. The benzimidazole derivative TUP-14 was obtained, 0.732 g of yellow solid, with a yield of 63%. The structural formula of benzimidazole derivative TUP-14 is:

(2) Identification results:

mp293-295°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ8.01-7.99 (d, J=8Hz, 1H), 7.21-7.19 (m, 2H), 7.04-7.02 (d, J= 8Hz, 1H), 6.94-6.92(m, 2H), 6.76-6.74(d, J=8Hz, 1H), 6.40-6.36(t, J=16Hz, 1H), 5.89(s, 2H), 4.15-4.04 (m, 3H), 3.13-3.07(d, J=24Hz, 2H), 1.87-1.85(d, J=8Hz, 2H), 1.65-1.61(m, 2H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ168.3, 155.9, 144.6, 138.7, 119.5, 118.6, 115.4, 115.2, 114.1, 46.0, 45.5, 30.6.

Example 17: Preparation and structure identification of benzimidazole derivative TUP-15

(1) Preparation method:

In a 100mL round bottom flask, add benzimidazole derivative TUP-14 (0.621g, 1.69mmol), bis(trichloromethyl) carbonate (triphosgene, 0.65g, 2.3mmol), 1-butyl 3-Methylimidazolium tetrafluoroborate ([BMI _m ]BF ₄ , 14 mL), iodine (0.04 g, 0.169 mmol), heated to 80°C, and reacted for 19 h. Cool down to 0°C, add water 20mL, saturated sodium thiosulfate solution 20mL, triethylamine 1mL, off-white solid precipitates, filter, wash with water 100mL, ethyl acetate 100mL, methyl tert-butyl ether 200mL, vacuum at 40°C Oven dry. The benzimidazole derivative TUP-15 was obtained as off-white solid 0.576 g with a yield of 87%. The structural formula of benzimidazole derivative TUP-15 is:

(2) Identification results:

¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.36-7.34 (m, 2H), 7.17-7.15 (m, 3H), 6.92-6.90 (d, J=8Hz, 1H), 6.54-6.50 ( t, J=16Hz, 1H), 6.11(s, 1H), 4.08-4.05(d, J=12Hz, 3H), 3.80(s, 3H), 3.36-3.31(t, J=20Hz, 2H), 1.97 -1.95 (d, J=8Hz, 2H), 1.72-1.64 (m, 2H); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO) δ 168.2, 151.9, 146.9, 139.5, 132.8, 122.1, 119.9, 114.4, 113.9, 111.9, 111.5, 109.5, 55.6, 45.6, 45.3, 30.2; MS (ES) ( _m /z) calcd for _{C21H22N5O3 392.1722} , found _392.1702 .

Example 18: Preparation and structure identification of benzimidazole derivative TUP-16

(1) Preparation method:

Dry the 100mL round-bottom flask in an oven, pump and change the air three times to fill the bottle with nitrogen, insert a nitrogen balloon, add benzimidazole derivative TUP-15 (0.520g, 1.63mmol), add redistilled dichloromethane 16.3 mL, cooled to -20°C, slowly added 1M dichloromethane boron tribromide (16.3mL, 16.3mmol), stirred at room temperature for 8h, cooled to -20°C, slowly added methanol 32.5mL to quench the reaction, stirred at room temperature for 10h. The solvent was spin-dried, washed with 20 mL of water and 100 mL of ethyl acetate, and dried in a vacuum oven at 40°C. The benzimidazole derivative TUP-16 was obtained, 0.484 g of yellow solid, with a yield of 84%. The structural formula of benzimidazole derivative TUP-16 is:

(2) Identification results:

mp265-266°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.45-7.43 (m, 2H), 7.38-7.36 (d, J=8Hz, 1H), 7.30-7.28 (m, 2H) , 7.13-7.11(d, J=8Hz, 1H), 7.03-6.99(t, J=16Hz, 1H), 5.20-5.14(t, J=24Hz, 1H), 4.22-4.19(d, J=12Hz, 2H), 3.52-3.45(t, J=28Hz, 2H), 2.77-2.68(m, 2H), 1.86-1.83(d, J=12Hz, 2H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO )δ 162.4, 149.8, 149.6, 144.0, 129.9, 128.8, 123.4, 122.5, 118.8, 117.1, 115.0, 111.3, 48.5, 46.9, 26.6.

Example 19: Preparation and structure identification of benzimidazole derivative TUP-17

(1) Preparation method:

In a 100mL round bottom flask, add benzimidazole derivatives TUP-10 (2.023g, 10mmol), 2-amino-3-methoxybenzoic acid (1.588g, 9.5mmol), 1-hydroxybenzotriazole (HOBT, 4.054g, 30mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 2.3g, 12mmol), DMF 30mL, stirred at room temperature for 1h, then added DIPEA ( 7mL, 40mmol), react at room temperature for 7h. 1000 mL of water was added, extracted with ethyl acetate, the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The benzimidazole derivative TUP-17 was obtained, 1.165 g of off-white solid, with a yield of 34%. The structural formula of benzimidazole derivative TUP-17 is:

(2) Identification results:

mp260-261°C; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.22-7.19 (t, J=12Hz, 2H), 6.94-6.92 (m, 2H), 6.89-6.87 (d, J= 8Hz, 1H), 6.71-6.70(d, J=4Hz, 1H), 6.63-6.59(t, J=16Hz, 1H), 4.82(s, 2H), 3.81(s, 3H), 3.55(m, 8H ); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO) δ 168.5, 155.8, 146.6, 135.1, 119.6, 119.1, 115.7, 110.9, 55.5, 46.0; MS(ES) (m/z) calcd for C ₁₉ H _{22N5O2 352.1773} , found _352.1753 .

Example 20: Preparation and structural identification of benzimidazole derivative TUP-18

(1) Preparation method:

Dry the 100mL round-bottomed flask, pump and ventilate it three times to fill the bottle with nitrogen, insert a nitrogen balloon, add benzimidazole derivative TUP-17 (0.537g, 1.5mmol), distilled dichloromethane 15mL, cool down To -20°C, slowly add 1M dichloromethane in boron tribromide solution (15mL, 15mmol), stir at room temperature for 8h, cool down to -20°C, slowly add methanol 30mL to quench the reaction, and stir at room temperature for 10h. Spin to dry the solvent, add 200 mL of water, wash with 400 mL of ethyl acetate, adjust the pH to 7 with 5M sodium hydroxide solution to precipitate the product, add 300 mL of water for washing, and dry in a vacuum oven. The benzimidazole derivative TUP-18 was obtained as a yellow solid 0.414 g with a yield of 83%. The structural formula of benzimidazole derivative TUP-18 is:

(2) Identification results:

mp275-277℃; ¹ H NMR (400MHz, (CD ₃ ) ₂ SO) δ7.22-7.19 (m, 2H), 6.94-6.92 (m, 2H), 6.74-6.72 (d, J=8Hz, 1H) , 6.58-6.56(m, 1H), 6.50-6.46(t, J=16Hz, 1H), 5.76(s, 1H), 4.63(s, 2H), 3.55(s, 8H); ¹³ C NMR (101MHz, (CD ₃ ) ₂ SO) δ 168.8, 155.8, 144.5, 138.3, 134.3, 119.7, 118.3, 115.9, 114.6, 54.9, 46.0.

Example 21: Calcium imaging fluorescence detection experiment

Add 50 μL of poly-L-ornithine hydrobromide solution to a 96-well plate, place it at room temperature for 2 hours, remove the poly-L-ornithine hydrobromide solution, wash each well twice with 50 μL of sterile water, and put the common HEK293 stably transfected cells expressing TRPC4β and μ opioid receptors were seeded in 96-well plates at 4×10 ⁴ /well, and incubated overnight in a CO ₂ incubator at 37°C. The next day, after the cells had grown to cover the 96-well plate, the cell culture medium was removed, and Fluo-4(AM) (50 μL, 2 μM) was added, and incubated for one hour at 37°C in the dark to allow the fluorescent dye to fully enter the cells. Both the compound and DAMGO were configured in HBSS, starting at 100 μmol/L, three-fold serial dilution, and set up 8 gradient concentration groups, namely 100 μmol/L, 33.33 μmol/L, 11.11 μmol/L, 3.70 μmol/L, 1.23 μmol/L , 0.41 μmol/L, 0.136 μmol/L, 80 μL of compounds with different concentrations were added to each well of the compound plate, and a group without compounds was set as a negative control. Then suck off Fluo-4(AM), wash with HBSS 3 times to remove extracellular residual Fluo-4(AM), add 80 μL of HBSS, and then put the cell plate and compound plate into the FDSS/μCELL drug screening system, Changes in fluorescence intensity under excitation at 480 nm and emission at 540 nm were detected. Before the experiment starts, detect the fluorescence change within 30s, then the instrument automatically adds 20 μL of the compound to each well of the cell plate, and then detects for 120 seconds, then adds DAMGO (20 μL, 1 μM) to each well for stimulation, and tests for 180 s.

Calcium imaging fluorescence detection experiment results: TUP-01IC50＝0.33μM; TUP-02IC50＝15.24μM; TUP-03IC50＝2.8μM; TUP-04IC50＝10.43μM; -07IC50=65.48μM; TUP-08IC50=80.76μM; TUP-09IC50=18.29μM; TUP-10EC50=0.71μM; 14IC50=0.154μM; TUP-15IC50=95.45μM; TUP-16IC50=2.84μM; TUP-17IC50=83.23μM; TUP-18IC50=95.68μM.

Example 22: Verification experiment on the anti-morphine addiction effect of benzimidazole derivative TUP-14

The present invention adopts conventional gavage experiment design, after gavage administration of benzimidazole derivatives to experimental rats, subcutaneous injection of 10 mg/kg of morphine or cocaine, using classical rat sensitization and conditioned place preference animal models for evaluation of addiction, To observe the effects of benzimidazole derivatives on the expression of relapse behavior and sensitization behavior after withdrawal of conditioned place preference in rats, and to evaluate the inhibitory effect of benzimidazole derivatives on morphine addiction and morphine addiction withdrawal Afterwards, the anti-relapse effect.

The results showed that the conditioned place preference and sensitization were formed in rats not given benzimidazole derivatives; after being treated with X benzimidazole derivatives, the formation of conditioned place preference and sensitization was inhibited, indicating that benzimidazole derivatives It can inhibit the formation of morphine addiction; at the same time, after treatment with benzimidazole derivatives, it can inhibit the relapse after withdrawal of conditioned place preference and sensitization, indicating that benzimidazole derivatives can inhibit the relapse after withdrawal of morphine addiction. Suck. Especially TUP-14 has the best inhibitory effect on morphine addiction.

Addictive drugs described in the present invention include narcotic drugs and psychotropic drugs etc., and narcotic drugs include opioids, cocaines, marijuana etc.; Amphetamines, the hallucinogen ergot diethylamine, etc.; others include alcohol, tobacco, and volatile organic solvents. Addictive drugs act on the mesolimbic dopamine system and its projections in the brain reward circuit, including the ventral tagmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). etc., causing reward effects, long-term neuroplastic changes, leading to strong psychological craving and spiritual dependence (Nestler, 2004, 2005, Hyman et al., 2006), all addictive substances have similar mechanisms of action, so their effects are similar.

Example 23: Validation experiment on the effect of benzimidazole derivative TUP-14 on the sensitization of rats to morphine and cocaine

In this example, TUP-14, a derivative of benzimidazoles, is selected as a drug against high-incidence activities of morphine and cocaine addiction. By establishing a sensitized rat model of morphine and cocaine, the effects of TUP-14, a derivative of benzimidazoles on rats are investigated. Improvement of hyperspontaneous activity induced by morphine and cocaine using the following steps:

(1) Materials and methods

Drugs and reagents: Morphine (Qinghai Pharmaceutical Factory); animal SPF grade SD male rats, body weight 220-250g. Provided by the Hubei Laboratory Animal Research Center, the animal certificate number is NO.42000600012016, and the production license number is SCXK (E) 2015-2018. Rat feed was purchased from the Experimental Animal Center of Wuhan University.

(2) Experimental method

Animal grouping and treatment: Rats were randomly divided into four groups, which were normal saline + solvent group, normal saline + TUP-14 administration group, morphine + solvent group, and morphine + XXX administration group.

Animal modeling: the day before the experiment (day 0), the experimental rats were measured for baseline activity, and were randomly divided into 4 groups (n=10) according to the measurement results; on the first to fifth day of the experiment, normal saline + solvent control group And morphine or cocaine+solvent control group all in advance 45 minutes intragastric administration of normal saline (2ml/kg), then normal saline-solvent control group subcutaneous injection of normal saline (1ml/kg), morphine or cocaine-solvent control group subcutaneous injection of morphine ( 10mg/kg) or cocaine (10mg/kg); the normal saline-TUP-14 administration group and the morphine or cocaine-TUP-14 administration group were administered TUP-14 (10, 100mg/kg) 45 minutes in advance, and then Normal saline+TUP-14 administration group subcutaneous injection of physiological saline (1ml/kg) and morphine or cocaine+TUP-14 administration group subcutaneous injection of morphine (10mg/kg); after administration, all animals recorded spontaneous activity 60 minute. This experiment was repeated for 5 days. Then they were withdrawn for 5 days, and challenged by subcutaneous injection of a small dose of morphine (5 mg/kg) on the 10th day of the experiment to detect changes in their spontaneous activity behavior.

Test indicators: After injecting morphine, the rats in each group were put into a spontaneous activity detection box (as shown in Figure 1) to record spontaneous activities for 1 hour, and the computer program automatically recorded the total number of activities of the rats, recording once every 5 minutes. After the formation of sensitization, the rats were withdrawn in the cage environment for 5 days, challenged with a small dose of morphine, and put the rats into a spontaneous activity box to record their spontaneous activity.

(3) Experimental results

The effect of benzimidazole derivative TUP-14 on the sensitization of rats to morphine or cocaine: the baseline conditions of SD rats in each group were roughly the same. Rats in the normal saline control group (normal saline+solvent control, normal saline+XXX administration) were administered intragastrically with blank solvent and TUP-14, so as to exclude the influence of TUP-14 itself on the spontaneous activities of the animals. During the sensitization modeling process, the rats in the morphine or cocaine-solvent group continued to be given blank solvent, and the test showed that the excitability of the rats continued to increase, and the sensitization effect was obvious; Rats were given high doses of TUP-14 (0, 10, 100mg/kg), observed that the spontaneous activity of the rats was significantly lower than that of the experimental group not given TUP-14, and the excitability was significantly reduced, indicating that TUP-14 has no effect on morphine or cocaine. Sensitization formation also has a certain inhibitory effect, as shown in Figure 2.

Example 24: Validation experiment on the effect of benzimidazole derivative TUP-14 on psychological craving in rats addicted to morphine

In this example, benzimidazole derivative TUP-14 was selected as a drug against psychological craving for morphine addiction, and a morphine conditioned place preference (conditioned place preference, CPP) model was established to study the benzimidazole derivative TUP-14 on morphine addiction. The role of environmental cues in inducing relapse after psychological cravings are formed.

1. Materials and methods

Drugs and reagents Morphine (Qinghai Pharmaceutical Factory);

Animal SPF grade male SD rats, weighing 220-250g. Provided by the Hubei Laboratory Animal Research Center, the animal certificate number is NO.42000600012016, and the production license number is SCXK (E) 2015-2018. Rat feed was purchased from the Experimental Animal Center of Wuhan University.

2. Experimental equipment

Conditional position preference instrument (developed by Institute of Materia Medica, Chinese Academy of Medical Sciences): The experiment is automatically controlled by computer. The device is a conditioned place preference box consisting of three boxes: two side chambers and a middle chamber, as shown in Figure 3. The three chambers are separated by movable partitions, both inside and out are black. Among them, box A and box B are located on both sides of the middle box, with the same size. There is a square formed by 9 yellow light-emitting diodes on the side wall of box A. The bottom plate is made of stainless steel bars, and the bottom plate of box B is made of stainless steel mesh. Rats stay in each box and the number of times of entry and exit can be transmitted to the computer through data, and automatically collect and record behavioral data.

3. Grouping and handling of animals:

Rats were randomly divided into four groups, namely normal saline + solvent group, normal saline + benzimidazole derivatives TUP-14 administration group and morphine + solvent group, morphine + benzimidazole derivatives TUP-14 administration group Group.

4. Experimental method

(1) Establishment of morphine CPP model

Basic value test: On the first day, open the passage between the three boxes, start the CPP program on the computer, put the rats in the middle room, let them move freely in the three boxes for 15 minutes, and record the time they stay in each room synchronously by the computer .

Conditioned place preference training: from the 2nd to the 5th day, the passage between the three boxes was closed. At 8:00 in the morning, the experimental group was subcutaneously injected with morphine (10 mg/kg) and placed on the drug side for 45 minutes; the control group was injected with normal saline (1 ml/kg) and placed on the non-medicated side for 45 minutes. At 16:00 in the afternoon, both the experimental group and the control group were injected with normal saline, the experimental group was placed on the non-drug side, and the control group was placed on the drug side, both for 45 minutes. The drug side of each rat was fixed. Rats in each group were then returned to their home cages.

Morphine CPP test: CPP test was performed on day 6, similar to the basal value test phase. Open the passage between the three boxes, do not give any injection, start the CPP program on the computer, put the rats in the middle room, let them move freely in the three boxes for 15 minutes, and record the time they stay in each room synchronously by the computer. The preference score (CPP score) was defined as the difference between the time spent in the room with the drug and the time spent in the room without the drug. Compare the post-test value of CPP with the front-side value of the rat in the medicine box to determine whether the rat forms CPP. Rats that did not form CPP were excluded according to the measured value of CPP, and the animals were matched and divided into four groups: normal saline + solvent control group, normal saline + TUP-14 administration group, morphine + solvent control group, morphine +TUP-14 administration group.

(2) Establishment of environmental cues-induced drug-seeking behavior model

On the 7th day of the experiment, each group of rats was given solvent and TUP-14 (100mg/kg) by intragastric administration for 15 minutes, and then put into the medicine box, and after staying for 10 minutes, the rats returned to the cage environment. After 24 hours, the effect on conditioned place preference was detected, and the flow chart of the drug administration experiment is shown in Figure 4A.

(3) Morphine CPP Retest

24 hours and 7 days after the end of the previous experiment, that is, on the 8th and 14th day of the experiment, test the preference of the rats to the medicine box respectively, 15 minutes, the same as the basic value test stage, observe the changes in the rats' CPP score . From the 9th day to the 13th day in the middle, no treatment was done to the rats.

(4) Ignition of Morphine CPP

Twenty-four hours after the test on day 14, ie on day 15, a small dose of morphine (3 mg/kg, i.p.) was used for ignition. Ten minutes after the morphine injection, the rats were put into the middle box to start the 15-minute CPP value test.

Detection Indicator:

After the rats were trained and lighted with a small dose, the conditioned place preference score (CPP Score) of the rats was detected to reflect the changes in the psychological craving behavior of the rats after addiction. If the CPP Score decreased, the addictive behavior was inhibited.

5. Experimental results

After the formation of conditioned place preference in the rats, the CPPScore was measured after administration of normal saline and TUP-14 before environmental cues re-exposure, and it was found that the conditioned place preference of the rats in the normal saline control group still existed; while in the TUP-14 administration group, the CPP Score decreased significantly, The psychological craving caused by the drug administration environment was suppressed, and it was not ignited after 1 week, as shown in Figure 4. The difference between the administration group and the control group is significant, indicating that the benzimidazole derivative TUP-14 can improve the symptoms of morphine addiction.

6. Experimental conclusion

The benzimidazole derivative TUP-14 can effectively inhibit the psychological craving behavior induced by environmental cues and improve the sensitization effect caused by morphine. Therefore, the benzimidazole derivative TUP-14 has the effect of anti-morphine addiction, and the action is specific, and it is a kind of potential drug addiction treatment drug with good anti-drug addiction effect.

Example 25: Application of Benzimidazole Derivatives

The present invention provides the application of the above-mentioned benzimidazole derivatives in the preparation of drugs for preventing and/or treating drug addiction.

At the same time, the present invention provides the application of the above-mentioned benzimidazole derivatives in the preparation of drugs for preventing and/or treating relapse after withdrawal of addictive drugs.

Preferably, the addictive drug refers to any one or two or more of narcotic drugs or psychotropic drugs or alcohol, tobacco, and volatile organic solvents.

Preferably, the narcotic drugs include opioids, cocaine, and marijuana, and the opioids include opium from natural sources and the active ingredient morphine extracted therefrom, as well as heroin, a product obtained by processing the active ingredients, and synthetic products similar to opioids.

In summary, the present invention provides a kind of benzimidazole derivative and its preparation method and application. Benzimidazole derivatives can inhibit the formation of morphine addiction. After establishing morphine and cocaine sensitized rat models, it can be seen that the spontaneous activity of rats in the morphine or cocaine-TUP-14 group was significantly lower than that of the non-administered benzimidazole derivatives TUP-14 In the experimental group, the excitability was significantly reduced, indicating that the benzimidazole derivative TUP-14 also has a certain inhibitory effect on the sensitization of morphine or cocaine, and the benzimidazole derivative prepared by this application can effectively reduce the morphine addiction withdrawal The drug has a significant effect on suppressing the withdrawal symptoms of morphine, and has wide practicality and development value in the technical field of pharmaceutical preparation.

As mentioned above, the present invention can be better realized. The above-mentioned embodiment is only a description of the preferred implementation of the present invention, and does not limit the scope of the present invention. Various changes and improvements made by technicians to the technical solutions of the present invention shall fall within the scope of protection determined by the present invention.

Claims (10)

1. A benzimidazole derivative having a structure shown in (I): Wherein, R ₁ =H, R ₂ =H or O, X=C or N or O or S, n=0 or 1. 2. A kind of benzimidazole derivative as claimed in claim 1, is characterized in that, described R ₁ is any one in alkyl substituent, phenyl substituent, benzyl substituent. 3. a kind of benzimidazole derivative as claimed in claim 1, is characterized in that, described R ₂ is any one in alkyl substituent, phenyl substituent, benzyl substituent, acyl substituent . 4. a kind of benzimidazole derivative as claimed in claim 1, is characterized in that, the preparation method of described benzimidazole derivative adopts the following technical steps: 5. the benzimidazole derivative as claimed in claim 1, is characterized in that, described benzimidazole derivative is selected from the one in TUP-1 to TUP-18: 6. Use of a benzimidazole derivative in the preparation of a drug for preventing and/or treating drug addiction. 7. The use of a benzimidazole derivative in the preparation of a drug for preventing and/or treating relapse after withdrawal of addictive drugs. 8. as the application of the benzimidazole derivative described in any one of claim 6 or 7, it is characterized in that, described addictive drug refers to narcotic drug or psychotropic drug or alcohol, tobacco, volatile organic solvent any one or two or more of them. 9. the application of benzimidazole derivatives as claimed in claim 8 is characterized in that, described narcotic drug comprises opiates, cocaines, marijuana, and opioids comprises the opium of natural source and the active ingredient extracted therefrom Morphine, as well as heroin, a product obtained by processing the active ingredients, is a synthetic product that acts like opioids. 10. The benzimidazole derivative according to any one of claims 6 or 7, wherein the benzimidazole derivative is selected from one of TUP-1 to TUP-18: