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Thiophene 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof

A technology of tetrahydroisoquinoline and tetrahydroisoquinoline hydrochloride, which is applied in the field of medicinal chemical synthesis and pharmacotherapeutics, can solve the problem of affecting the pharmacokinetic properties of chemotherapy drugs, the toxicity of small molecules of inhibitors cannot be ignored, and the increase Drug toxicity and side effects and other problems, to achieve good biological activity, high yield, improve the effect of drug efficacy

Inactive Publication Date: 2021-03-12
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the first three generations of inhibitors, there are also drug molecules that have entered the clinical trial stage, but the main problems they face in clinical application are: 1. Poor selectivity of inhibitors to P-gp; 2. Insufficient inhibitory activity of inhibitors on P-gp; 3. The toxicity of small molecules of inhibitors cannot be ignored; 4. Inhibitors affect the pharmacokinetic properties of chemotherapy drugs, increasing the toxic and side effects of drugs, etc.
At present, there is no alternative strategy to deal with multidrug resistance in clinic, and it is urgent to develop new and efficient selective P-gp inhibitors for clinical use

Method used

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  • Thiophene 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof
  • Thiophene 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof
  • Thiophene 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: 5-(3'-methoxyphenyl)-2-(2'-H-3,4-dihydro-6,7-methoxyisoquinoline)thiophene-2-carboxamide ( Ⅰ-2) Preparation

[0047]

[0048] (1) Add 5g (24.1mmol) of 5-bromo-2-thiophenecarboxylic acid (II) and 10mL (156.2mmol) of dichloromethane into a 100mL three-necked flask equipped with a thermometer, stir and dissolve to form a clear solution. 7.5 g (63.0 mmol) of thionyl chloride was added with stirring. Raise the temperature to 60°C, react for 8 hours and concentrate to dryness with a rotary evaporator to remove excess solvent and unreacted thionyl chloride, and the resulting crude product 5.37g (24.0mmol) is 5-bromo-2-thiophene chloride (Ⅲ ), yield: 98%. for the next reaction.

[0049] (2) Add 1.72g (7.5mmol) and 10mL (156.2mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride into a 50mL three-necked flask equipped with a thermometer Dichloromethane, stirred and cooled to 0°C, and 15 mL of 4mol / L sodium hydroxide aqueous solution was added drop...

Embodiment 2

[0058] Cytotoxicity of thiophene-containing 2,5-disubstituted-tetrahydroisoquinoline compounds shown in embodiment 2, formula I to MCF-7 / ADR

[0059] Cell line: MCF-7 / ADR (human breast cancer cell line resistant to doxorubicin, obtained from Nanjing Kaiji Biotechnology Development Co., Ltd.).

[0060] Sample test concentration: 5 μM, dissolved in RPMI 1640 medium containing 1% DMSO+10% fetal bovine serum and added.

[0061] Test method: MTT (tetramethyl azolium salt) method was used to test the cell proliferation activity of the compound.

[0062] MCF-7 / ADR cells were incubated with RPMI 1640 medium (purchased from Gbico) containing 10% fetal bovine serum at 37°C, 5% CO 2 cultured under saturated humidity conditions. Cells in the logarithmic growth phase were taken at 1×10 5 / mL density in 96-well culture plate, 100 μL per well at 37 ° C, 5% CO 2 Cultured under the condition of saturated humidity, divided into blank control group and test compound group. Different compoun...

Embodiment 3

[0065] Example 3. Research on the multidrug resistance reversal activity of thiophene 2,5-disubstituted-tetrahydroisoquinoline compounds represented by formula (I) on MCF-7 / ADR cells.

[0066]Cell line: MCF-7 / ADR (human breast cancer cell line resistant to doxorubicin, obtained from Nanjing Kaiji Biotechnology Development Co., Ltd.).

[0067] Test compound test final concentration: 5 μM, dissolved in RPMI 1640 medium containing volume concentration 1% DMSO+10% calf serum and then added.

[0068] Positive control drug: verapamil, dissolved in RPMI 1640 medium containing volume concentration 1% DMSO+10% calf serum and then added.

[0069] Test method: The MTT (tetramethyl azolium salt) method was used to conduct the cell proliferation activity test of the compound and doxorubicin in combination.

[0070] MCF-7 / ADR cells were incubated with RPMI 1640 medium (purchased from Gbico) containing 10% calf serum at 37°C, 5% CO 2 cultured under saturated humidity conditions. Cells in ...

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Abstract

The invention discloses a thiophene 2, 5-disubstituted tetrahydroisoquinoline compound as shown in a formula (I), a preparation method thereof and application thereof as a tumor multidrug resistance reversal agent. Pharmacological experiment results show that the compound provided by the invention has excellent tumor multidrug resistance reversal activity and sensitization chemotherapy drug activity, and can be clinically used as a malignant tumor multidrug resistance reversal agent and a chemotherapy drug sensitizer.

Description

[0001] (1) Technical field [0002] The invention belongs to the field of medicinal chemical synthesis and pharmacotherapeutics, and in particular relates to a preparation method of thiophene 2,5-disubstituted-tetrahydroisoquinoline compounds and an application in medicine. [0003] (2) Background technology [0004] An important reason for the failure of clinical treatment of malignant tumors is the multidrug resistance (MDR) exhibited by the tumor with the increase of chemotherapy course (Curr Med Chem. 2012, 19, 1946-2025.). The overexpression of P-glycoprotein (P-glycoprotein, P-gp) in the ATP-binding (ABC) transporter family on the surface of tumor cell membrane is the most widely studied mechanism of tumor MDR production (Eur J Med Chem.2016,118,219- 229.). As a common type of transmembrane protein, P-gp is currently considered to be overexpressed on the cell membrane of tumor cells with the progress of chemotherapy, which is the biggest obstacle to the continuous effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/06A61P35/00A61P35/04
CPCA61P35/00A61P35/04C07D409/06
Inventor 王鸿李亚胜魏斌叶欣艺鲍晓泽孙漩嵘
Owner ZHEJIANG UNIV OF TECH
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