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Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application

A technology of farnesyl thiosalicylic acid and farnesyl thiosalicylate, applied in the field of biomedicine

Active Publication Date: 2014-06-18
福建金化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to obtain a compound with stronger anti-tumor activity or anti-inflammatory response than FTA, the present invention discloses a new class of phenylacrylic acid derivatives of FTA and pharmaceutically acceptable salts thereof. any reports of

Method used

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  • Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application
  • Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application
  • Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 2-methoxy-4-((E)-3-(2-morpholinoethylamino)-3-oxapropenyl)phenyl-farnesylthiosalicylate (I 1 ) preparation

[0088] Preparation of (E)-3-(4-hydroxy-3-methoxyphenyl)-N-(2-morpholinoethyl)acrylamide (5a)

[0089] 2-Morpholinoethylamine (2.03 g, 15.5 mmol) and triethylamine (4.70 g, 46.5 mmol) were dissolved in 20 mL of anhydrous CH 2 Cl 2 In ice bath, slowly dropwise add acetyl ferulic acid chloride (6a, 1.31g, 5.16mmol) in CH 2 Cl 2 Solution 20mL, remove the ice bath after dripping, continue to stir at room temperature, spot the plate until the reaction is complete. Concentrate the reaction solution, dissolve the concentrate in 10 mL of methanol, add 1N NaOH solution, continue to stir at room temperature for 2 hours, adjust the pH to neutral, concentrate to make sand, and pass through the column (PE:AE=1:1~1:4). 1.17 g of a colorless transparent viscous liquid was obtained, with a yield of 74%.

[0090] 2-Methoxy-4-((E)-3-(2-morpholinoethylamino)-3-oxapro...

Embodiment 2

[0093] Example 2 2-methoxy-4-((E)-3-(2-(diethylamino)propylamino)-3-oxapropenyl)phenyl-farnesyl thiosalicylate (I 2 ) preparation

[0094] Preparation of (E)-N-(2-(diethylamino)propyl)-3-(4-hydroxyl-3-methoxyphenyl)acrylamide (5b)

[0095] Referring to the synthesis method of (5a), acetyl ferulic acid chloride (6a, 1.31g, 5.16mmol) was reacted with diethylaminopropylamine (2.02g, 15.5mmol) to obtain 1.06g of colorless transparent viscous liquid (67 %).

[0096] 2-Methoxy-4-((E)-3-(2-(diethylamino)propylamino)-3-oxapropenyl)phenylfarnesylthiosalicylate (I 2 ) preparation

[0097] Refer to (I 1 ) synthesis method, from FTA (0.32g, 0.49mmol), 5b (0.16g, 0.51mmol) to obtain a colorless transparent viscous liquid 0.22g, yield 71%.

[0098] 1 H NMR (CDCl 3 ,300MHz):δ8.25(d,1H,J=7.8Hz,Ar-H),7.66(m,1H,Ar-H),7.51(m,2H,Ar-H,COCH=C H ),7.36(m,2H,Ar-H),7.23(m,2H,Ar-H),6.39(d,1H,J=16.2Hz,COCH),5.35(m,1H,SCH 2 C H ),5.09(m,2H,2×CH 2 C H =CCH 3 ),3.59(m,5H,SCH 2 ,OCH 3 ),2.50...

Embodiment 3

[0099] Example 3 2-Methoxy-4-((E)-3-(4-methylpiperazin-1-yl)butoxy)-3-oxapropenyl)phenyl farnesylthio water Salylate (I 3 ) preparation

[0100] Preparation of (E)-4-bromobutyl-3-(3-acetoxy-4-hydroxyphenyl)acrylate (2a)

[0101] Ferulic acid (1a, 5g, 25.8mmol) was dissolved in 50mL of acetone, 1,4-dibromobutane (21.6g, 100mmol), 10mL of Et 3 N, heated at an external temperature of 50°C for 4h. After cooling to room temperature, a large amount of white solid precipitated, filtered, the filtrate was concentrated, and column chromatography [ethyl acetate: petroleum ether (60-90°C) = 1:4 (V:V)] was eluted to obtain a light yellow needle-like solid 6.85g (77%), mp 96-98°C.

[0102] Preparation of 2-methyl-4-((E)-3-(4-bromobutoxy)-3-oxapropenyl)-phenyl-farnesylthiosalicylate (3a)

[0103] Dissolve FTA (2.4 g, 6.70 mmol), 2a (2.31 g, 7.04 mmol), DMAP (0.70 g, 5.70 mmol) in 30 mL of anhydrous CH 2 Cl 2 , stirring, slowly drop DCC (1.66g, 8.04mmol) in CH under ice bath 2 Cl 2 ...

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Abstract

The invention discloses a phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as a preparation method and an application. The phenyl acrylic acid farnesyl thiosalicylic acid derivative is a compound of a formula (I) in the specification, wherein X1 represents O or NH; X2 represents O or NH; n is equal to 1- 3; R represents H or OCH3. By coupling ferulic acid and p-hydroxy cinnamic acid fragments with carboxyl of FTA, the capability of a target molecule in scavenging free radicals is improved, the anti-tumor effect of the molecule is improved, and then a compound with anti-tumor activity or anti-inflammatory activity higher than those of FTA is obtained.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to novel farnesylthiosalicylic acid derivatives of phenylacrylic acid and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their Medical use, especially in the preparation of anti-tumor drugs and anti-inflammatory response drugs. Background technique [0002] All-trans farnesyl thiosalicylic acid (abbreviation: FTA, trade name: Salirasib) is the first farnesyl-based Ras protein inhibitor, which can competitively replace F-Ras and F-Ras muteins with half Lectin binds and inhibits Ras-induced downstream signaling pathways (including Raf and P13K signaling pathways) and mTOR (a stimulator of tumorigenesis, which can rely on or independently open P13K signaling pathways), thereby promoting tumor cell apoptosis and inhibiting tumors cell growth. Studies have shown that FTA has inhibitory effects on breast cance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/13C07C323/62C07D295/088C07D295/205C07D233/60C07D233/61C07C319/20A61K31/625A61K31/618A61P35/00A61P29/00
CPCC07C231/02C07C235/34C07C319/20C07C323/62C07D233/60C07D233/61C07D295/088C07D295/13C07D295/205
Inventor 凌勇吴彩霞张洁王雪敏赵颖陈娟李祥华徐辰俊
Owner 福建金化科技有限公司
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