Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof

A technology of dihydroisoquinoline and compound, applied in organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problems of limited application, large cardiovascular side effects, affecting plasma pharmacokinetics, etc.

Active Publication Date: 2016-11-16
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 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 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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  • Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof
  • Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof
  • Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Preparation of compound (i)

[0070] Under ice bath, freshly prepared aromatic acid chloride (20mmol) was slowly added to a solution of substituted or unsubstituted anthranilic acid (30mmol) in pyridine (15ml), stirred under ice bath for 30min, and then continued to stir at room temperature for 12h. The reaction solution was poured into water (200ml), stirred vigorously until a large amount of solids were precipitated, left to stand, filtered with suction, washed with water (20ml×5), and dried to obtain the product (i) as a white solid.

Embodiment 2

[0072] Preparation of Compound (ii)

[0073] Add the prepared compound (i), ammonia water (15ml) and ethanol (20ml) into a pressure-resistant bottle, seal it, heat to 80°C for 12h, cool, filter with suction, wash with water (15ml×3), and dry to obtain a white Solid product (ii).

Embodiment 3

[0075] Preparation of compound (iii)

[0076] The prepared compound (ii) (1 equiv) was added to thionyl chloride (10 equiv), and after adding a catalytic amount of DMF, it was heated to 50° C. for 6 h. Excess thionyl chloride was distilled off under reduced pressure to obtain a light yellow solid residue. Add the residue to an appropriate amount of 1N sodium hydroxide solution, stir and add an equal volume of dichloromethane for extraction, wash the organic layer with water and saturated brine, dry over anhydrous sodium sulfate, filter with suction, and evaporate under reduced pressure The product (iii) is obtained as a white or pale yellow solid after solvent removal.

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Abstract

The invention relates to compounds shown as a general formula (I) and salt thereof. The compounds have strong reverse tumor multidrug resistance (MDR) effect, activity of part of the compounds is far higher than verapamil, and the compounds have low cytotoxicity. The invention further relates to a medicinal preparation containing the compounds. A series of the compounds shown as the general formula (I) and the pharmaceutically acceptable salt thereof are synthesized.

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. At present, multidrug resistance has become a major reason for the failure of tumor chemotherapy. 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 mechanism of tumor multidrug resistance is diverse, involving complex molecular biological basis, which has not been fully resolved yet, but the overexpression of tumor cell transmembrane ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D405/14A61K31/517A61P35/00A61P35/02
Inventor 黄文龙钱海崔建刘保民邱倩倩吴玉祥潘渺博
Owner CHINA PHARM UNIV
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