Dimethoxy tetrahydroisoquinoline-benzo six-membered ring compound as well as preparation method and application thereof

Abstract

The invention discloses a dimethoxy tetrahydroisoquinoline-benzo six-membered ring compound and a preparation method and application thereof.The compound has good biological activity, can effectively inhibit the P-gp function and remarkably improve the accumulation amount of chemotherapeutic drugs in drug-resistant cells, can also remarkably improve the sensitivity of drug-resistant tumor cells to adriamycin, and has a good application prospect. The excellent MDR reversal activity is shown. The compound can be used for development and utilization of drugs for treating multidrug resistance of malignant tumor cells caused by multidrug resistance related proteins. A new candidate compound is provided for solving the clinical problem of tumor MDR, and an important foundation is laid for developing a new generation of efficient and low-toxicity P-gp inhibitor. The compounds with unique structures are expected to become novel drugs for overcoming multidrug resistance of tumors, and have wide clinical application prospects.

Description

(I) Technical Field

[0001] This invention belongs to the fields of pharmaceutical chemistry synthesis and pharmacotherapeutic science, and specifically relates to a dimethoxytetrahydroisoquinoline-benzohexacyclic compound and its preparation method and drug application method. (II) Background Technology

[0002] Multidrug resistance (MDR) in tumors is a major cause of chemotherapy failure in clinical practice, and drug efflux mediated by the overexpression of P-glycoprotein (P-gp) is one of the most important resistance mechanisms. As an ATP-dependent efflux pump, P-gp actively removes various chemotherapeutic drugs from cells, leading to insufficient intracellular drug concentrations and thus resistance. Studies have shown that inhibiting P-gp function can significantly improve the sensitivity of drug-resistant tumor cells to chemotherapeutic drugs. However, currently reported P-gp inhibitors generally suffer from poor selectivity, insufficient inhibitory activity, and significant toxic side effects, severely limiting their clinical application. (III) Summary of the Invention

[0003] The purpose of this invention is to provide a series of novel bis(methoxytetrahydroisoquinoline)-benzo6-membered ring compounds, their preparation methods, and applications. Based on a structural optimization strategy, this invention designs and synthesizes a series of novel bis(methoxytetrahydroisoquinoline)-benzo6-membered ring compounds. In vitro activity evaluation shows that this series of compounds possesses good biological activity, effectively inhibiting P-gp function, significantly increasing the accumulation of chemotherapeutic drugs in drug-resistant cells, and significantly enhancing the sensitivity of drug-resistant tumor cells to doxorubicin, exhibiting excellent MDR reversal activity. These compounds can be used in the development and utilization of drugs to treat multidrug resistance in malignant tumor cells caused by multidrug resistance-associated proteins. This provides new candidate compounds for solving the clinical challenge of tumor MDR and lays an important foundation for the development of a new generation of highly effective and low-toxicity P-gp inhibitors. These structurally unique compounds are expected to become novel drugs for overcoming tumor multidrug resistance and have broad clinical application prospects.

[0004] The technical solution adopted in this invention is:

[0005] In a first aspect, the present invention provides a dimethoxytetrahydroisoquinoline-benzohexane six-membered ring compound having a structure as shown in formula I, II, III, IV or V:

[0006]

[0007] In Formula I, the R group can be one or more substitutions, and the R group can be methoxy, ethoxy, propoxy, butoxy, phenoxy, trifluoromethoxy, methylenedioxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, methyl, ethyl, propyl, butyl, tert-butyl, nitro, or cyano; the R group in Formula II, III, IV, or V is the same as the R group in Formula I.

[0008] Preferably, R is hydrogen, 2-methoxy, 3-methoxy, 4-methoxy, 4-ethoxy, 4-propoxy, 4-tert-butoxy, 4-trifluoromethoxy, 4-phenoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, or 3,4,5-trimethoxy.

[0009] More preferably, the compound is one of the following:

[0010]

[0011] Secondly, the present invention provides a method for preparing the aforementioned bis(methoxytetrahydroisoquinoline)-benzo6-membered ring compound, the method comprising the following steps:

[0012]

[0013]

[0014]

[0015] phenylboronic acid

[0016] S1. In the presence of a diluent and an acid-binding agent, compounds of formulas VI, VII, VIII, IX, and X are reacted with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, and the intermediates of formulas VI-1, VII-2, VIII-3, IX-4, and X-5 are purified and isolated.

[0017] S2. In the presence of a diluent, a base, and a catalyst, intermediates of formulas VI-1, VII-2, VIII-3, IX-4, and X-5 are reacted with phenylboronic acid, and the resulting final products I, II, III, IV, and V are purified and separated. The catalyst is a zero-valent or divalent palladium catalyst. The base is an organic or inorganic base. The R group in the phenylboronic acid is the same as the R group in formula I.

[0018] That is, experiencing the following reaction:

[0019]

[0020] The diluent is an inert organic solvent. As a preferred embodiment, the diluent is selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformaniline, N-methylpyrrolidone, hexamethylphosphoric triamine, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, or diethylene glycol monoethyl ether. As a more preferred embodiment, the diluent is dichloromethane, benzene, toluene, or tetrahydrofuran.

[0021] The presence of an acid-binding agent is beneficial to the reaction. As a preferred embodiment, the acid-binding agent is preferably sodium hydroxide, potassium carbonate, sodium ethoxide, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene. As an most preferred embodiment, the acid-binding agent is a 10% (w / w) aqueous solution of sodium hydroxide.

[0022] The presence of a base favors the reaction. As a preferred embodiment, the base is an organic or inorganic base, such as sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, trimethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene. As a most preferred embodiment, the base is potassium carbonate.

[0023] The presence of a catalyst is beneficial to the reaction. As a preferred embodiment, the catalyst is Pd(OAc)₂, PdCl₂, Pd(MeCN)₂Cl₂, Pd(PPh₃)₄, or Pd(TFA)₂. As an optimal embodiment, the catalyst is tetrakis(triphenylphosphine)palladium, i.e., Pd(PPh₃)₄.

[0024] Preferably, in S1, the reaction temperature for the reaction of compounds of formulas VI, VII, VIII, IX, and X with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride can be carried out in a wide range depending on the choice of diluent, preferably 0~100°C, more preferably 0~30°C. The reaction time is 12~48 hours, more preferably 24 hours.

[0025] Preferably, the molar ratios of the compounds represented by formulas VI, VII, VIII, IX, and X in S1 to 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and the acid-binding agent are 1:1-3 (preferably 1:1) and 1:1-5 (preferably 1:3), respectively; the volume of the diluent used is 1-5 mL / mmol (preferably 2 mL / mmol) based on the molar amount of the compounds represented by formulas VI, VII, VIII, IX, and X.

[0026] Preferably, in S2, the reaction temperature for the intermediates of formulas VI-1, VII-2, VIII-3, IX-4, and X-5 with phenylboronic acid can be carried out in a wide range depending on the choice of diluent, preferably 80~160℃, more preferably 85~90℃. The reaction time is 8~20 hours, more preferably 12 hours.

[0027] Preferably, the molar ratios of intermediates VI-1, VII-2, VIII-3, IX-4, and X-5 in S2 to phenylboronic acid, base, and catalyst are 1:1-5 (preferably 1:1), 1:1-5 (preferably 1:3), and 1:0.001-0.01 (preferably 1:0.005), respectively; and the volume of the diluent used is 1-5 mL / mmol (preferably 4 mL / mmol) based on the molar amount of the intermediates.

[0028] All of the above intermediates or target compounds can be purified using conventional separation techniques such as recrystallization or chromatographic separation.

[0029] Preferably, the purification and separation method for S1 is as follows: The reaction solution is filtered, the organic layer is washed with water and dried overnight with anhydrous magnesium sulfate, the desiccant is filtered out and the solvent is evaporated to obtain a pale yellow solid; the pale yellow solid is dissolved in dichloromethane and purified by silica gel chromatography column (silica gel particle size 200-300 mesh, column inner diameter 4 cm, height 8 cm), the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, gravity elution is performed, the elution rate is about 1 / 200 column volume per minute, and the eluent with V petroleum ether / V ethyl acetate = 1 / 1 is collected to obtain the intermediate.

[0030] Preferably, the purification method for S2 is as follows: the reaction solution is filtered, the organic layer is washed with water and dried overnight with magnesium sulfate; after filtering out the desiccant, the solvent is evaporated to obtain a white solid; the white solid is dissolved in dichloromethane and purified by silica gel chromatography column (silica gel particle size 200-300 mesh, column inner diameter 2 cm, height 7 cm), the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, gravity elution is performed, the elution rate is about 1 / 200 column volume per minute, and the eluent with V petroleum ether / V ethyl acetate = 1 / 1 is collected to obtain the compound.

[0031] More preferably, the compound is prepared according to the following steps:

[0032] S1. In a 50 mL three-necked flask equipped with a thermometer, add 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and dichloromethane a, stir and cool to 0 °C. Add an aqueous solution containing sodium hydroxide a dropwise, controlling the dropping rate to maintain the temperature at around 0 °C. After the addition is complete, stir for 30 min, maintaining the system temperature at 0 °C. Simultaneously, add a solution of dichloromethane b containing compounds of formulas VI, VII, VIII, IX, and X, and an aqueous solution containing sodium hydroxide b, controlling the dropping rate to ensure both are added simultaneously. After the addition is complete, slowly raise the temperature to room temperature and react at 25 °C for 18–24 h. Filter the reaction solution, wash the organic layer with water, and dry it overnight with anhydrous magnesium sulfate. After filtering out the desiccant, evaporate the solvent to obtain a pale yellow solid. Dissolve the pale yellow solid in dichloromethane and then perform chromatography on a silica gel column (silica gel particle size 200-300 mesh, column inner diameter 4 cm, height 8 cm). (cm) Purification, the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, gravity elution, and the eluent of petroleum ether and ethyl acetate in a volume ratio of 1:1 is collected to obtain the intermediate; dichloromethane a and dichloromethane b are both dichloromethane, the letters themselves have no meaning, the volume ratio of the two is 2:1, and the total volume used is 2 mL / mmol based on the molar amount of the compounds shown in formulas VI, VII, VIII, IX, and X; sodium hydroxide a and sodium hydroxide b are both sodium hydroxide, the letters themselves have no meaning, the molar ratio of the two is 2:1; the total molar ratio of the compounds shown in formulas VI, VII, VIII, IX, and X to 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and sodium hydroxide is 1:1 and 1:3, respectively;

[0033] S2. In a 50 mL three-necked flask equipped with a thermometer, under nitrogen protection, phenylboronic acid, tetra(triphenylphosphine)palladium, potassium carbonate, the intermediate, and toluene were added sequentially, and the reaction was carried out at 85 °C for 12 h. After the reaction was completed, the reaction solution was filtered, the organic layer was washed with water, dried with magnesium sulfate overnight, the desiccant was filtered off, and the solvent was evaporated to obtain a white solid. The white solid was dissolved in dichloromethane and purified by silica gel chromatography column (silica gel particle size 200-300 mesh, column inner diameter 2 cm, height 7 cm). The eluent was petroleum ether and ethyl acetate in a volume ratio of 1:1. Gravity elution was performed, and the eluent of petroleum ether and ethyl acetate in a volume ratio of 1 was collected to obtain the compound.

[0034] Thirdly, the present invention provides the application of the aforementioned bis(methoxytetrahydroisoquinoline)-benzohexacyclic compound in the preparation of P-gp inhibitors.

[0035] Preferably, the inhibitor comprises a pharmaceutically acceptable molecule.

[0036] Fourthly, the present invention provides the application of the aforementioned bismethoxytetrahydroisoquinoline-benzohexacyclic compound in the preparation of tumor multidrug resistance reversal agents or tumor metastasis inhibitors.

[0037] Preferably, the tumor cell line is a human breast cancer doxorubicin-resistant cell line (MCF-7 / ADR).

[0038] The compounds described in this invention can be used in combination with antitumor drugs, including alkylating agents (such as cyclophosphamide or cisplatin), antimetabolites (such as 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (such as camptothecin or topotecan), microtubule inhibitors (such as paclitaxel or vincristine), DNA inserters (such as doxorubicin or daunorubicin), and lysine kinase inhibitors (such as gefitinib). By combining these compounds with antitumor drugs, the sensitivity of multidrug-resistant tumor cells to antitumor drugs is enhanced, thereby improving the efficacy of chemotherapy.

[0039] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0040] This invention discloses a bis(methoxytetrahydroisoquinoline)-benzo6-membered ring compound, which exhibits good biological activity and can be used as a P-gp inhibitor or a tumor multidrug resistance reversal agent. The preparation method of the bis(methoxytetrahydroisoquinoline)-benzo6-membered ring compound is simple and yields high efficiency. Experiments have shown that, at concentrations without cytotoxicity when used alone, it exhibits a significant sensitizing effect on drug-resistant cancer cell lines when combined with antitumor drugs. Specifically, the combination of compound I or II with doxorubicin hydrochloride effectively enhances the efficacy of doxorubicin hydrochloride against the human breast cancer doxorubicin-resistant cell line (MCF-7 / ADR). This invention expands the application prospects of tetrahydroisoquinoline structures as tumor multidrug resistance reversal agents. (iv) Description of the attached drawings

[0041] Figure 1 The image shows the proton NMR spectrum of the compound represented by Formula I-3. (V) Detailed Implementation Methods

[0042] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0043] Unless otherwise specified, the reagents and methods involved in the examples are all commonly used in the art.

[0044] The room temperature mentioned in this invention refers to 25-30℃.

[0045] Example 1: Preparation of (6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)(5-(3-methoxyphenyl)-naphth-2-yl)methyl ketone (Ⅰ-3)

[0046] In a 50 mL three-necked flask equipped with a thermometer, 7.5 mmol of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and 10 mL of dichloromethane were added. The mixture was stirred and cooled to 0 °C. 6 mL of a 10% (wt.) sodium hydroxide aqueous solution containing 15 mmol of sodium hydroxide was added dropwise, controlling the dropping rate to maintain the temperature at approximately 0 °C. After the addition was complete, the mixture was stirred for 30 min. While maintaining the system temperature at 0 °C, 5 mL of a dichloromethane solution containing 7.5 mmol of 5-bromo-2-naphthoic acid (VI) and 3 mL of a 10% (wt.) sodium hydroxide aqueous solution containing 7.5 mmol of sodium hydroxide were added dropwise simultaneously. The dropping rate was controlled to ensure both solutions were added at the same time. After the addition was complete, the mixture was slowly raised to room temperature and reacted at 25 °C for 18–24 h. The reaction solution was filtered, the organic layer was washed with water, and dried overnight with anhydrous magnesium sulfate. After filtering out the drying agent, the solvent was evaporated to obtain a pale yellow solid. The pale yellow solid was dissolved in 1.0 mL of dichloromethane and purified by silica gel chromatography (silica gel particle size 200-300 mesh, column inner diameter 4 cm, height 8 cm) using petroleum ether and ethyl acetate in a 1:1 volume ratio. Gravity elution was performed at a rate of approximately 1 / 200 column volume per minute. The eluent with a volume ratio of V petroleum ether / V ethyl acetate was collected to yield 7.0 mmol of intermediate IV, namely 5-bromo-2-(2'-H-3,4-dihydro-6,7-methoxyisoquinoline)naphthalene-2-carboxamide, which was used in the next step of the reaction.

[0047] In a 50 mL three-necked flask equipped with a thermometer, under nitrogen protection, 5 mmol of 3-methoxyphenylboronic acid, 0.025 mmol of tetrakis(triphenylphosphine)palladium, 15 mmol of potassium carbonate, and 5 mmol of intermediate V were added sequentially with 20 mL of toluene. The reaction was carried out at 85 °C for 12 h. After the reaction was completed, the reaction solution was filtered, the organic layer was washed with water and dried overnight with magnesium sulfate. After filtering out the drying agent, the solvent was evaporated to obtain a white solid. The white solid was dissolved in 0.5 mL of dichloromethane and purified by silica gel chromatography (silica gel particle size 200-300 mesh, column inner diameter 2 cm, height 7 cm) with petroleum ether and ethyl acetate in a 1:1 v ratio as eluent. Gravity elution was performed at a rate of approximately 1 / 200 column volume per minute. The eluent with a volume ratio of V petroleum ether / V ethyl acetate = 1 / 1 was collected to give 4.8 mmol of compound I-3. The overall yield of the three-step reaction was 89%. The 1H NMR spectrum is shown below. Figure 1 The data is shown in Table 2.

[0048] Example 2, Preparation of the compound

[0049] Following a method similar to that in Example 1, only the R in phenylboronic acid was replaced as shown in Table 1 to obtain the corresponding compounds represented by formulas I, II, III, IV, and V. The appearance and yield of these compounds are listed in Table 1, and the 1H NMR results are listed in Table 2. It can be seen from the above that the structures of the above compounds are correct, and they are all compounds represented by formulas I, II, III, IV, and V.

[0050] Table 1. Physicochemical constants of compounds represented by formulas I, II, III, IV, and V.

[0051]

[0052]

[0053] Table 2. 1H NMR spectral data of the compounds represented by formulas I, II, III, IV, and V.

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] Example 3: Study on the multidrug resistance reversal activity of the dimethoxytetrahydroisoquinoline-benzohexacyclic compounds shown in Formulas I, II, III, IV and V against MCF-7 / ADR cells.

[0062] Test compounds: Compounds prepared in Examples 1 and 2, 5 μM, in DMSO (dimethyl sulfoxide).

[0063] Positive control drug: Verapamil, 5 μM, in DMSO solvent.

[0064] Experimental method: The cell proliferation activity assay of the compound in combination with doxorubicin was performed using the MTT (tetramethylazozazole salt) method.

[0065] Complete culture medium: RPMI 1640 medium containing 10% fetal bovine serum

[0066] MCF-7 / ADR cells were cultured in complete medium at 37°C and 5% CO2 saturated humidity. Cells in the logarithmic growth phase were harvested and cultured at a concentration of 1×10⁻⁶ cells / mL. 5100 μL of the compound was seeded at a density of 1 / mL in 96-well plates, divided into a blank control group, a test compound group, and a positive control group. The plates were cultured at 37℃ and 5% CO2 saturated humidity. The test compound group was treated with 5 μM of the test compound and 1 μM of doxorubicin; the positive control group was treated with 5 μM of Verapamil and 1 μM of doxorubicin; and the blank control group was given an equal volume of complete culture medium. After 48 h of culture, MTT working solution was added, and the optical density was read at 490 nm using a microplate reader to calculate the effect of the compounds on cell viability. Triple replicates were performed. The antiproliferative activity of the compounds described in formulas I, II, III, IV, and V in combination with doxorubicin against MCF-7 / ADR cells was calculated, and the results are shown in Table 3.

[0067] Table 3. Antiproliferative activity of compounds represented by formulas I, II, III, IV, and V in combination with doxorubicin against MCF-7 / ADR cells.

[0068]

[0069] As can be seen from Table 3, most of the compounds shown in Formula I have good activity in reversing multidrug resistance in tumor cells. Among them, compounds I-5, I-7, I-8, III-3, IV-5, V-7, V-13 and V-14, when combined with doxorubicin, showed an inhibition rate of more than 50% against MCF-7 / ADR, and their multidrug resistance reversal activity was better than that of the control drug Verpamil. Among them, compound I-7, when combined with doxorubicin, showed the best anti-multidrug resistant tumor proliferation activity and has good application prospects.

Claims

1. A bis(methoxytetrahydroisoquinoline)-benzohexacyclic compound, characterized in that, The dimethoxytetrahydroisoquinoline-benzohexacyclic compounds have structures as shown in formulas I, II, III, IV or V: In Formula I, the R group can be one or more substitutions, and the R group can be methoxy, ethoxy, propoxy, butoxy, phenoxy, trifluoromethoxy, methylenedioxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, methyl, ethyl, propyl, butyl, tert-butyl, nitro, or cyano; the R group in Formulas II, III, IV, or V is the same as the R group in Formula I.

2. The compound according to claim 1, characterized in that, The R is hydrogen, 2-methoxy, 3-methoxy, 4-methoxy, 4-ethoxy, 4-propoxy, 4-tert-butoxy, 4-trifluoromethoxy, 4-phenoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, or 3,4,5-trimethoxy.

3. A method for preparing the bis(methoxytetrahydroisoquinoline)-benzohexacyclic compound of claim 1, characterized in that, The method includes the following steps: phenylboronic acid S1. In the presence of a diluent and an acid-binding agent, compounds of formulas VI, VII, VIII, IX, and X are reacted with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, and the intermediates of formulas VI-1, VII-2, VIII-3, IX-4, and X-5 are purified and isolated. S2. In the presence of a diluent, a base, and a catalyst, intermediates of formulas VI-1, VII-2, VIII-3, IX-4, and X-5 are reacted with phenylboronic acid, and the resulting final products I, II, III, IV, and V are purified and separated; the catalyst is a zero-valent or divalent palladium catalyst; the base is an organic or inorganic base; and the R group in the phenylboronic acid is the same as the R group in formula I of claim 1.

4. The preparation method according to claim 3, characterized in that, The diluents mentioned in steps S1 and S2 are all inert organic solvents selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformaniline, N-methylpyrrolidone, hexamethylphosphoric triamine, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, or diethylene glycol monoethyl ether.

5. The preparation method according to claim 3, characterized in that, The acid-binding agent is selected from sodium hydroxide, potassium carbonate, sodium ethoxide, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene; the base is selected from sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, trimethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene; the catalyst is Pd(OAc)2, PdCl2, Pd(MeCN)2Cl2, Pd(PPh3)4, or Pd(TFA)2.

6. The preparation method according to claim 3, characterized in that, In S1, the reaction temperature is 0~100℃ and the reaction time is 12~48 hours; the molar ratios of the compounds shown in formulas VI, VII, VIII, IX, and X to 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and the acid-binding agent are 1:1-3 and 1:1-5, respectively; the volume of diluent used is 1-5 mL / mmol based on the molar amount of the compounds shown in formulas VI, VII, VIII, IX, and X.

7. The preparation method according to claim 3, characterized in that, In S2, the reaction temperature is 80~160℃ and the reaction time is 8~20 hours; the molar ratios of intermediates VI-1, VII-2, VIII-3, IX-4, and X-5 to phenylboronic acid, base, and catalyst are 1:1-5, 1:1-5, and 1:0.001-0.01, respectively; the volume of the diluent used is 1-5 mL / mmol based on the molar amount of the intermediate.

8. The use of the bis(methoxytetrahydroisoquinoline)-benzohexacyclic compound of claim 1 in the preparation of P-gp inhibitors.

9. The use of the bis(methoxytetrahydroisoquinoline)-benzohexacyclic compound of claim 1 in the preparation of tumor multidrug resistance reversal agents or tumor metastasis inhibitors.

10. The application as described in claim 9, characterized in that, The tumor cell line mentioned is the human breast cancer doxorubicin-resistant cell line MCF-7 / ADR.

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