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N-phenyl alkoxy dibenzazepine compound as well as preparation method and medical application thereof

A technology of phenylalkoxydibenzoazepines and compounds, which is applied in the field of N-phenylalkoxydibenzoazepines compounds, can solve problems such as low activity of Bifendate, and achieve excellent P-glycoprotein Inhibitory effect

Pending Publication Date: 2022-07-29
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But as a P-gp inhibitor, Bifendate is less active

Method used

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  • N-phenyl alkoxy dibenzazepine compound as well as preparation method and medical application thereof
  • N-phenyl alkoxy dibenzazepine compound as well as preparation method and medical application thereof
  • N-phenyl alkoxy dibenzazepine compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] 2-(4,10-Dimethoxy-6,8-dihydro-7H-[1,3]dioxo[4',5':3,4]benzo[1,2-c] [1,3]dioxo[4',5':5,6]benzo[1,2-e]azepin-7-yl)phenyl)ethan-1-ol (A1)

[0079] Step 1: Dissolve biphenyl diester (5g, 12mmol) in 200mL tetrahydrofuran, cool to 0°C in ice bath, add LiAlH in batches 4 (1.357g, 36mmol), naturally warmed to room temperature for reaction. The reaction was monitored by TLC. After the reaction was completed, the ice bath was cooled to 0°C, and 2 mL of water, 6 mL of 15% NaOH aqueous solution and 2 mL of water were added to the reaction solution in turn, stirred (off-white suspension) for 10 min, and an appropriate amount of anhydrous sodium sulfate was added and stirred for 30 minutes. Suction filtration after -50min, and the filter cake was washed with methanol several times. The filtrate was concentrated under reduced pressure, dispersed with water, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium...

Embodiment 2

[0083] 7-(4-(2-Bromoethyl)phenyl)-4,10-dimethoxy-7,8-dihydro-6H-[1,3]dioxoxa[4',5' :3,4]benzo[1,2-c][1,3]dioxanone[4',5':5,6]benzo[1,2-e]azepine (A2 )

[0084] Step 1-3: Obtain A1 according to the method of Step 1-3 described in Example 1.

[0085] Step 4: 2-(4,10-Dimethoxy-6,8-dihydro-7H-[1,3]dioxo[4',5':3,4]benzo[1,2 -c][1,3]dioxo[4',5':5,6]benzo[1,2-e]azepin-7-yl)phenyl)ethan-1-ol ( A1) (500 mg, 1.08 mmol) was dissolved in 20 mL of dichloromethane, then phosphorus tribromide (123.5 μL, 1.3 mmol, density: 2.85 g / mL) was added, 0.2 mL of pyridine was added after five minutes, and a metal bath was added under nitrogen protection. The temperature was gradually raised to 45°C, and condensed to reflux. After 2 hours, the reaction of the starting materials was monitored by TLC, and the reaction was completed. Water was added to disperse, the reaction solution was extracted with dichloromethane, the organic layer was washed with saturated sodium bicarbonate and distilled water...

Embodiment 3

[0087] 4-(4,10-Dimethoxy-6,8-dihydro-7H-[1,3]dioxetane[4',5':3,4]benzo[1,2- c][1,3]dioxolane[4',5':5,6]benzo[1,2-e]azepin-7-yl)benzyl alcohol (A3)

[0088] Following the similar method of step 1-3 described in Example 1, use intermediate product III (500 mg, 1.0 mmol), 2-aminobenzyl alcohol (615.7 mg, 5.0 mmol), triethylamine (1.43 mL, 10 mmol) to react to obtain white The title compound (315 mg, 68.2%).

[0089] 1 H NMR (400MHz, DMSO-d 6 )δppm: 7.16-7.07(m, 2H), 6.97-6.88(m, 2H), 6.74(s, 2H), 6.02(d, J=1.0Hz, 2H), 5.96(d, J=1.0Hz, 2H) ), 4.43(d, J=12.9Hz, 2H), 4.34(d, J=5.5Hz, 2H), 3.78(s, 6H), 3.52(d, J=12.8Hz, 2H); ESI-MS: m / z 450.1[M+H] + .

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Abstract

The invention discloses an N-phenyl alkoxy dibenzazepine compound as well as a preparation method and medical application thereof, belongs to the field of biological medicines, and particularly relates to an N-phenyl alkoxy dibenzazepine compound as shown in a general formula I or pharmaceutically acceptable salt thereof. Pharmacological experiment results show that the compound has excellent P-glycoprotein inhibitory activity, tumor multidrug resistance reversal activity and anti-tumor metastasis activity, and can be clinically used as a tumor multidrug resistance reversal agent and a tumor metastasis inhibitor.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapy, in particular to a class of N-phenylalkoxydibenzoazepine compounds. The compounds can be used for the preparation of P-glycoprotein inhibitors and tumor multidrug resistance reversal agents. The present invention also relates to a preparation method of such compounds and a pharmaceutical combination containing them. Background technique [0002] The resistance of tumor cells to a variety of anticancer drugs with different structures and mechanisms is called multidrug resistance (MDR), which is the main reason for the failure of tumor chemotherapy (Canc.Lett.2014,347,159-166 ; Mol. Pharm. 2011, 8, 1996-2011; Methods Mol. Biol. 2010, 596, 47-76.). The mechanism of tumor MDR production is very complex, including abnormal changes in intracellular enzymes (Arch Pharm Res 2005, 28, 249-268.), abnormal expression of apoptosis-regulating genes (especially p53 and Bcl-2) (Cell, 19...

Claims

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Application Information

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IPC IPC(8): C07D491/153A61P35/00A61K31/55
CPCC07D491/153A61P35/00
Inventor 谷小珂蒋春雨曾美凤蒋云翔张志宇
Owner XUZHOU MEDICAL UNIV
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