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Triazole-N-phenethyl tetrahydronaphthalene isoquinoline compounds and, preparation method and application thereof

A technology of dihydroisoquinoline and compound, which can be used in organic chemistry, drug combination, antitumor drugs, etc., and can solve problems such as large cardiovascular side effects and limited application.

Inactive Publication Date: 2018-01-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the first-generation inhibitors are represented by verapamil and cyclosporine A, and these inhibitors have relatively large cardiovascular side effects; the activity of the second-generation inhibitors is enhanced, such as Valspodar and Biricodard, but these inhibitors obviously affect the The plasma pharmacokinetics of anticancer drugs used in combination with it limits its clinical application; the third-generation inhibitors are compounds designed and developed based on the study of structure-activity relationship, and these compound inhibitors have better activity and selection sex, such as Elacridar, Tariquidar and WK-X-34, etc.
However, due to the emergence of various side effects, there is still no effective reversal agent used in clinical treatment

Method used

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  • Triazole-N-phenethyl tetrahydronaphthalene isoquinoline compounds and, preparation method and application thereof
  • Triazole-N-phenethyl tetrahydronaphthalene isoquinoline compounds and, preparation method and application thereof
  • Triazole-N-phenethyl tetrahydronaphthalene isoquinoline compounds and, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline (a)

[0072] Add p-nitrophenethyl bromide (2.42g, 10mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.41g, 10.5 mmol), anhydrous potassium carbonate (3.48g, 25.2mmol), acetonitrile 50ml. After heating to reflux for 18 hours, cool, filter, and wash the filter cake with dichloromethane. The filtrate was distilled under reduced pressure to remove the solvent to obtain a yellow solid. The solid was recrystallized from ethanol to obtain 2.76 g of a yellow needle-like crystalline solid with a yield of 81.2%.

[0073] 1H NMR (DMSO-d6, 300MHz) δ: 8.16-8.13 (d, J=8.7Hz, 2H), 7.57-7.53 (d, J=8.7Hz, 2H), 6.65(s, 1H), 6.62(s, 1H), 3.69(s, 6H), 3.53(s, 2H), 3.00-2.94(t, J=6.9Hz, 2H,), 2.75-2.68(m, 6H).

Embodiment 2

[0075] Preparation of 4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)aniline (b)

[0076] Add compound a (11.02g, 32.2mmol), ethanol / dichloromethane mixed solvent (1:1, 60mL), Pd / C (0.58g) into a 100ml single-necked bottle, and hydrogen reduction reaction at room temperature for 48h. Diatomaceous earth was used as a bedding layer for filtration, and the filter cake was washed with dichloromethane. The filtrate was evaporated under reduced pressure to remove the solvent to obtain a light yellow solid, which was recrystallized from dichloromethane / petroleum ether to obtain 7.9 g of off-white solid, with a yield of 79.0%.

[0077] 1H NMR (300MHz, CDCl3) δ: 7.05-7.01 (d, J=8.1Hz, 2H), 6.65-6.62 (d, J=8.1Hz), 6.60(s, 6H), 3.64(s, 2H), 3.57 (s, 2H), 2.85-2.68 (m, 8H).

Embodiment 3

[0079]2-(((1-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2 yl)ethyl)phenyl)-1H-1,2,3 Preparation of -triazol-4-yl)methyl)amino)phenyl)-4,5-dimethoxy-N-benzanilide (1)

[0080] (a) Preparation of 2-(4-azidophenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (c)

[0081] Compound b (4.8g15.36mmol) was dissolved in 30ml of 50% acetic acid, and sodium nitrite (1.38g19.97mmol) was slowly added dropwise at 0-5°C, keeping the temperature constant, and vigorously stirred for 50min. At 0-5°C, sodium azide (1.40 g, 21.51 mmol) was added in batches, and the temperature was kept constant, and stirring was continued for 1 h. The reaction solution was poured into 200ml of ice water, extracted with ethyl acetate (3*100mL), the organic layer was washed with water (3*60mL), saturated sodium bicarbonate (3*60mL), and saturated brine (3*50mL), Finally, anhydrous sodium sulfate was added for drying. The solvent was removed by distillation under reduced pressure to obtain 3.3 g of pink soli...

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Abstract

The invention relates to compounds as shown in a formula (I) and salt thereof. The compounds have relatively high action of reserving multidrug resistance (MDR) of tumors and the activity of part of the compounds is higher than that of verapamil, and the compounds have smaller cytotoxicity. The invention also relates to a drug preparation containing the compounds. A series of compounds as shown inthe formula (I) and pharmaceutically acceptable salt are synthesized. The formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of P-glycoprotein inhibitors. The invention also discloses its preparation method and the application of the compounds in multidrug resistance reversal agents. technical background [0002] Multidrug resistance (MDR) refers to the phenomenon that after tumor cells develop resistance to one antitumor drug, they also develop cross-resistance to other antitumor drugs with different structures and mechanisms of action. The occurrence of multidrug resistance is one of the main reasons for the failure of tumor chemotherapy, and it is also the most common and difficult problem in tumor treatment. Therefore, finding drugs to reverse MDR to inhibit the generation of multidrug resistance has become an urgent problem to be solved in tumor treatment. [0003] The mechanisms of tumor multidrug resistance are diverse, involving complex molecular biological foundations tha...

Claims

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Application Information

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IPC IPC(8): C07D401/10A61K31/4725A61P35/02
Inventor 黄文龙钱海赫斯曼李慧兰廖晨
Owner CHINA PHARM UNIV
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