Piplartine analogue, preparation method therefor and applications

A technology of perylene amide and analogs, applied in the field of medicinal chemistry, can solve the problems of limiting clinical application, large size, which can cause edema of adjacent renal tubules and glomerular epithelial cells, renal tubular hemorrhage, resistance, etc., and achieve good inhibitory activity , the effect of good medicinal prospects

Active Publication Date: 2015-09-16
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the nephrotoxicity of perylene amide is relatively large, which can cause edema and tubular hemorrhage in adjacent renal tubules and glomerular epithelial cells, which limits its clinical application (see Zhang Peng, Huang Qilai, Hua Zichun. Pharmacological studies of perylene amide Progress [J]. Chinese Herbal Medicine, 2012,43(1):2

Method used

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  • Piplartine analogue, preparation method therefor and applications
  • Piplartine analogue, preparation method therefor and applications
  • Piplartine analogue, preparation method therefor and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (E)-1-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-3-(3,4,5-trimethoxyphenyl)propan-2 Synthesis of -en-1-one (LHC-1)

[0031] 1.1 Synthesis of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid

[0032]

[0033] In a 500mL three-necked flask, add 3,4,5-trimethoxybenzaldehyde (10.0g, 51.0mmol), malonic acid (6.41g, 61.5mmol), pyridine (35mL), piperidine (2mL) and benzene (150mL), install an oil-water separator, and reflux at 110°C for 6h. TLC [V (chloroform): V (methanol) = 10:1 is the developer] detection shows that the reaction is basically complete, cooled to room temperature, added 75 (mL) saturated aqueous sodium carbonate solution, continued to stir for 30 min, separated, took the water phase, the water phase Adjust the pH to 4 with 3 mol / L hydrochloric acid, and a large amount of white solid precipitated; suction filtered, the filter cake was recrystallized with absolute ethanol, and dried to obtain 7.92 g of white solid, yield 65.2%, m.p.124.3-125.7°C.

[0034] 1.2(E...

Embodiment 2

[0039] (E)-1-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-3-(4-methoxyphenyl)prop-2-ene-1 -Synthesis of ketone (LHC-2)

[0040]

[0041] (E)-3-(4-methoxyphenyl)acrylic acid was synthesized according to the method 1.1 in Example 1, and (E)-1-(6,7-dihydrothiophene was obtained by operating according to the method 1.2 in Example 1 And[3,2-c]pyridin-5(4H)-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (LHC-2) light yellow solid, m.p.131.4~ 132.7°C; 1 H-NMR (CDCl 3 ,400MHz)δ:7.67(d,J=15.2Hz,1H,ArCH=),7.50(d,J=8.0Hz,2H,ArH),7.15(d,J=5.2Hz,1H,ThH),6.90( d,J=8.4Hz,2H,ArH),6.83-6.79(m,2H,ThH and-CH=),4.76(s,2H,Py-CH 2 ),3.97(br s,2H,Py-CH 2 ),3.84(s,3H,OCH 3 ),2.94(br s,2H,Py-CH 2 ); 13 C-NMR (CDCl 3 ,100MHz)δ:166.3,160.9,142.6,132.3,129.4,127.9,125.2,124.5,123.5,114.9,114.2,55.3,45.9,43.3,26.0; IR(KBr,cm -1 )υ: 3004.3, 2962.5, 2905.6, 1649.8, 1593.0, 1506.3, 1437.5, 1249.2, 1165.5, 1060.8, 1027.9, 980.1, 896.4, 824.6, 716.9; ESI-Mass for C 17 h 17 NO 2 S:m / z(M + +H)300.13.

Embodiment 3

[0043] (E)-1-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-3-(4-methylphenyl)prop-2-en-1- Synthesis of Ketones (LHC-3)

[0044]

[0045] (E)-3-(4-methylphenyl)acrylic acid was synthesized according to the method 1.1 in Example 1, and (E)-1-(6,7-dihydrothieno) was obtained according to the method 1.2 in Example 1 [3,2-c]pyridin-5(4H)-yl)-3-(4-methylphenyl)prop-2-en-1-one (LHC-3) white solid, m.p.145.8~147.2℃; 1 H-NMR (CDCl 3 ,400MHz) δ:7.69(d,J=15.6Hz,1H,ArCH=),7.45(d,J=7.6Hz,2H,ArH),7.19(d,J=8.0Hz,2H,ArH),7.15( d,J=5.2Hz,1H,ThH),6.89(d,J=15.6Hz,1H,-CH=),6.83(d,J=4.8Hz,1H,ThH),4.77(s,2H,Py- CH 2 ),3.97(br s,2H,Py-CH 2 ),2.95(br s,2H,Py-CH 2 ),2.37(s,3H,CH 3 ); 13 C-NMR (CDCl 3 ,100MHz)δ:166.2,142.9.139.9,132.4,129.5,127.6,125.2,124.5,123.5,116.5,116.2,45.9,43.2,25.9,21.4; IR(KBr,cm -1 )υ: 3076.1, 2923.6, 2833.9, 1643.9, 1596.0, 1518.3, 1455.5, 1452.5, 1323.9, 1219.3, 1054.8, 1013.0, 968.1, 812.6, 737.9, 660.1; ESI-Mass for C 17 h 17 NOS:m / z(M + +H)284.08.

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Abstract

The invention relates to the pharmaceutical chemistry field, and concretely relates to a piplartine analogue (I) or (II), a preparation method therefor and pharmaceutical compositions containing the piplartine analogue (I) and (II). The pharmacodynamic experiments prove that piplartine analogue can be used for treating or preventing thromboembolism diseases. The structural formulas of the piplartine analogue (I) and (II) are shown in the specification.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of perylene amide analogs, a preparation method and a pharmaceutical composition containing them. The perylene amide analogs of the present invention can be used for treating or preventing thromboembolic diseases. Background technique [0002] Piplartine is the main active ingredient in the perennial herbaceous vine plant Piplartine of the family Piperaceae. Studies have found that perylene amide and its derivatives can significantly inhibit the proliferation of tumor cells without affecting the physiological functions of normal cells (Raj L, Takao I, Aditi UG, et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS[J].Nature,475(2011):231~234; Li Shaolu. Use of perylene amide derivatives in the preparation of drugs for treating cancer and their pharmaceutical compositions CN102125552A (2011-07-20 )); Piperoneamide and ...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61P9/00A61P7/02A61P9/10
CPCC07D495/04
Inventor 李家明何广卫王杰储昭兴左键谢迪刘会财黄伟军
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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