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Tetrahydroindoloquinazoline compounds and application thereof

A technology of indoloquinazolines and compounds, applied in the field of tetrahydroindoloquinazolines, capable of solving problems such as low oral bioavailability

Active Publication Date: 2020-02-14
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, RUT has very low oral bioavailability, so We designed a series of derivatives of RUT (tetrahydroindoloquinazole morphine compounds) to improve their in vivo bioavailability while maintaining their anti-atherosclerotic, anti-inflammatory, etc. effect

Method used

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  • Tetrahydroindoloquinazoline compounds and application thereof
  • Tetrahydroindoloquinazoline compounds and application thereof
  • Tetrahydroindoloquinazoline compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the synthesis of TR2 and TR3

[0071] Add evodiamine (2.0g, 7mmol) into 100mL dry THF, slowly add lithium aluminum hydride (1.06g, 28mmol) in batches at room temperature, and stir at room temperature for 8h after the addition (the reaction system starts to turn yellow, The color gradually darkens to green, accompanied by fever).

[0072] Quench the reaction with 1M hydrochloric acid, filter with suction and wash with DCM, CH 3 OH washed, and the filtrate was collected. After most of the solvent was evaporated from the filtrate, the pH was adjusted to 8-9, extracted with DCM and dried. The filtrate and the extract were combined and concentrated, and separated by silica gel column chromatography using AcOEt:PE=1:4 as the eluent to obtain pure products TR2 and TR3 respectively.

[0073] 5,7,8,13,13b,14-Hexahydroindolo[2’,3’:3,4]pyrido[2,1-b]quinazoline (TR2)

[0074]

[0075] TR2 (16 mg, 3% relative yield), mp 181-183°C. MS(ESI m / z)276.21(M+H) + , 1...

Embodiment 2

[0079] Embodiment 2: the synthesis of indolo[2',3':3,4][2,1-b]quinazolin-5(13H)-ketone (TR4)

[0080]

[0081] At 50°C, dissolve evodiamine (1.44g, 5mmol) in 1,4-dioxane (20mL), and add dropwise DDQ (1.14g, 5mmol) in 1,4-dioxane (20mL) at 80°C. Oxycycline solution (red), the reaction system immediately turned green, and after reflux for 4 hours, the solvent was distilled off. Wash with 10% potassium hydroxide solution several times to remove DDQ-2H in the system, and after filtration, wash with 10% aqueous hydrochloric acid solution and pure water successively, and dry with suction to obtain the crude product. The crude product was washed with dichloromethane to give TR4 (0.67 g, 47% yield), a pale yellow solid, mp 282-284°C. MS(ESI,m / z)286.17(M+H) + , 318.30(M+Na) + .

[0082] 1 H NMR (400MHz, DMSO-d6) δ12.71(s, 1H, 13-NH), 8.64(d, J=7.6Hz, 1H, 4-H), 8.38(dd, J=1.2, 8.0 Hz, 1H ,9-H),8.18(d,J=8.0Hz,1H,7-H),7.94(td,1H,J=1.6,7.6Hz,2-H),7.86-7.84(m,2H,1, 3-2H),7.69 (d,J...

Embodiment 3

[0083] Example 3: 14-trifluoroacetyl-8,13,13b,14-dihydroindolo[2',3':3,4][2,1-b]quinazoline-5(7H )-Kone (TR6) Synthesis

[0084] 3-(2-(1H-3-indole)ethyl)-3H-quinazolin-4-one (1.45g, 5mmol) was suspended in 30mL of acetonitrile, and the ), a solution of trifluoroacetic anhydride (0.7mL, 5mmol) in acetonitrile was added dropwise, and the reaction system immediately became a transparent solution. The reaction continued for 2h, and a white solid precipitated out. The white solid was obtained by filtration, and the pure product TR6 was obtained after separation by silica gel column chromatography using AcOEt:PE=1:4 as the eluent.

[0085]

[0086] TR6 (0.63g), mp 199-201°C. HRMS(ESI m / z)calcd[M+H] + for C 20 h 13 o 2 N 3 f 3 384.1033 found 385.1637.

[0087] 1 H NMR (500MHz, DMSO-d6) δ11.41(s,1H,13-NH),7.90(d,J=7.5Hz,1H,4-H),7.67(t,J=7.5Hz, 1H,3 -H),7.38(t,J=7.5Hz,2H,2,9-2H),7.29(d,J=8.0Hz,1H,12-H),7.09(td,J=1.0,7.5Hz,2H ,10,11-H), 6.98(td,J=1.0,7.5Hz,1H,1-H),4.71(dd...

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Abstract

The invention relates to tetrahydroindoloquinazoline compounds and application thereof. Structures of the compounds are shown as a general formula (I) shown in the specification. The compounds are used for (1) preparing medicines for treating cardiovascular and cerebrovascular diseases; (2) preparing preparations for improving the expression of AMPK, ABCA1 and SR-BI; (3) preparing preparations foractivating the activity of a nuclear receptor NR, inhibiting the activity of NLRP3, the activity of IL-1[beta], the activity of NF-[kappa]B and the activity of MAPKs; (4) preparing preparations for promoting outflow of cell cholesterol; and (5) preparing anti-inflammatory medicines.

Description

technical field [0001] The invention belongs to the field of medical biotechnology, and specifically relates to a group of tetrahydroindoloquinazoline compounds and applications thereof. Background technique [0002] Atherosclerosis is a chronic disease characterized by lipid deposition and inflammation, and the inflammation of the vessel wall is an important reason for the development of atherosclerosis (Libby, P., et al., Inflammation inatherosclerosis. Nature, 2002.420 :868-874.). An important basis for inflammatory mediators in the process of atherosclerosis is the modification and deposition of lipids in plaques (Xu, S., et al., Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. Pharmacology & therapeutics, 2019.196 :15-43.). The early studies of anti-atherosclerotic drugs were mainly characterized by lipid-lowering, and statins were typical representatives. Although statins can effectively lower cholesterol, the effective ...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D471/22C07D498/14A61K31/4985A61K31/5365A61P29/00A61P9/00A61P9/10A61P3/06
CPCC07D471/14C07D471/22C07D498/14A61P29/00A61P9/00A61P9/10A61P3/06
Inventor 司书毅许艳妮王潇罗金雀李永臻刘超姜新海李依宁韩小婉李妍陈明华张晶甄心
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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