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Triazole phenethyl tetrahydro naphthalene compound and preparation method and application thereof

A technology of dihydroisoquinolines and compounds, applied in drug combination, organic chemistry, pharmaceutical formulations, etc., can solve problems such as limited application, major cardiovascular and other side effects, and changes in plasma pharmacokinetics

Active Publication Date: 2014-05-21
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first generation is represented by verapamil and cyclosporine A, these inhibitors lack sufficient specificity and affinity for P-gp, and have relatively large cardiovascular and other side effects
The activity of the second-generation inhibitors is enhanced, such as Valspodar and Biricodard, but these inhibitors significantly change the plasma pharmacokinetics of anticancer drugs combined with them, which limits their clinical application
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 phenethyl tetrahydro naphthalene compound and preparation method and application thereof
  • Triazole phenethyl tetrahydro naphthalene compound and preparation method and application thereof
  • Triazole phenethyl tetrahydro naphthalene compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Preparation of 2-(4-azidophenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2)

[0075] Compound 4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)aniline (3.72g, 12mmol) was dissolved in acetic acid and water at room temperature (12ml / 12ml) mixed solution. The temperature was cooled to -5°C in an ice-salt bath, and sodium nitrite (1.2 g, 17 mmol) was carefully added three times, the reaction solution was wine red, and kept stirring at 0-5°C for 30 min. The internal temperature was controlled at -5-5°C, and sodium azide (1.2 g, 18 mmol) was carefully added several times. During the addition process, the temperature rose violently, and a large number of bubbles were generated. After adding sodium azide, the reaction was continued at 0°C for 50 min. Add water (60ml) to the reaction solution for dilution, carefully add sodium carbonate to the reaction solution under stirring to adjust the pH to 7-8, extract with ethyl acetate (60ml×2), wash with saturated b...

Embodiment 2

[0079] N-(2-((1-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl)-ethyl)phenyl) -1H-1,2,3-triazol-4-yl)methoxy)phenyl)benzamide (I-1) preparation

[0080] Compound 2 (3.34g, 1mmol) and N-(2-(prop-2-yn-1-yloxy)phenyl)benzamide (0.25g, 1mmol) were dissolved in 75% methanol (40ml), and were added Sodium ascorbate (30mg) and copper sulfate (10mg), the reaction solution was stirred at room temperature for 24h, the precipitated solid was suction filtered, washed with methanol, and dried to obtain 0.52g of white solid, yield 80.2%, mp: 104-105°C.

[0081] 1 H NMR (300MHz, DMSO-d 6 )δ: 9.30 (s, 1H, CONH), 8.82 (s, 1H, NCH=C), 7.86 (d, J=6.9Hz, 1H, ArH), 7.72 (d, J=8.3Hz, 2H, ArH) , 7.56(d, J=8.4Hz, 2H, ArH), 7.48-7.45(m, 3H, ArH), 7.35(d, J=8.1Hz, 1H, ArH), 7.18(dd, J=7.0, 7.5Hz , 1H, ArH), 7.04-7.00 (m, 2H, ArH), 6.65, 6.62 (2s, 2H, ArH), 5.33 (s, 2H, OCH 2 ), 3.80 (s, 3H, OCH 3 ), 3.73-3.69 (m, 9H, 3OCH 3 ), 3.54(s, 2H, ArCH 2 N), 2.90-2.70 (m, 8H, 4CH 2 ); 13 C NMR (...

Embodiment 3

[0083] N-(2-((1-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl)-ethyl)phenyl) -1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2-methoxybenzamide (I-2) preparation

[0084] Referring to the preparation method of I-1 in Example 2, by compound 2 (1mmol) and 3,4-dimethoxy-N-(2-(prop-2-yn-1-yloxy)phenyl)benzyl Compound I-2 was prepared from amide (1 mmol) as a white solid with a yield of 64.5%; mp: 134-136°C.

[0085] 1 H NMR (300MHz, DMSO-d 6 )δ: 10.53 (s, 1H, CONH), 9.01 (s, 1H, NCH=C), 8.55 (d, J=7.1Hz, 1H, ArH), 8.08 (d, J=6.5Hz, 1H, ArH) , 7.81(d, J=8.3Hz, 2H, ArH), 7.54-7.48(m, 3H, ArH), 7.36(d, J=7.9Hz, 1H, ArH), 7.16-7.09(m, 3H, ArH) , 7.01 (dd, J=7.7, 7.5Hz, 1H, ArH), 6.65, 6.63 (2s, 2H, ArH), 5.37 (s, 2H, OCH 2 ), 3.69(s, 6H, 2OCH 3 ), 3.53 (s, 5H, OCH 3 , ArCH 2 N), 2.94-2.71 (m, 8H, 4CH 2 ); 13 C NMR (300MHz, DMSO-d 6 )δ:162.08,157.02,147.14,146.88,143.19,141.64,134.55,133.57,131.39,130.08,128.03,126.56,125.87,123.61,123.54,121.10,120.87,120.11,119.53,112.46,11...

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Abstract

The invention relates to a compound and a salt thereof in a general formula (I). The compound has strong reversal tumor multidrug resistance (MDR), and has small cytotoxicity, and the activity is much higher than that of verapamil. The invention also relates to a preparation method of the compound and a medicinal preparation containing the compound. The general formula (I) 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, a preparation method thereof and the application of the compounds in multidrug resistance reversal agents. Background technique [0002] The emergence of multidrug resistance (MDR) has become a major reason for the failure of tumor chemotherapy. Tumor multidrug resistance refers to the phenomenon that tumor cells simultaneously develop resistance to antitumor drugs with completely different chemical structures, targets and mechanisms of action. According to reports, the emergence of multidrug resistance often leads to the reduction of the efficacy of anticancer drugs used in clinical treatment, and finally leads to the failure of chemotherapy. Therefore, it has become an urgent problem to be solved in tumor treatment to find drugs that can reverse MDR to inhibit the generation of multidrug resistance. [0003] The generation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10C07D401/14A61K31/4725A61P35/00
CPCC07D401/10C07D401/14
Inventor 黄文龙钱海刘保民焦磊赵天笑邱倩倩
Owner CHINA PHARM UNIV
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