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Benzyl-substituted aniline compounds and their applications

An aniline compound and compound technology are applied in the preparation of aminohydroxy compounds, the preparation of cyanide reaction, the preparation of organic compounds, etc., which can solve the problems of uncontrolled cell proliferation and the like, and achieve the effect of good drug prospects.

Active Publication Date: 2016-08-17
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The mutation of Ras protein makes Ras protease continue to be activated, cell proliferation is out of control, leading to tumor formation

Method used

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  • Benzyl-substituted aniline compounds and their applications
  • Benzyl-substituted aniline compounds and their applications
  • Benzyl-substituted aniline compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 4-(3-ethoxy-4-(2-fluorobenzyloxy)-5-bromobenzylamino)phenol (1)

[0031]

[0032] The synthetic route of compound 1 is as follows:

[0033]

[0034] Synthesis of 3-ethoxy-4-hydroxy-5-bromobenzaldehyde (1.1)

[0035] 3-Ethoxy-4-hydroxybenzaldehyde (6.64 g, 40.0 mmol) was dissolved in acetic acid (80 mL) and fully dissolved. Then, liquid bromine (2.46 mL) was added dropwise to the reaction solution. After the dropwise addition, the reaction was carried out at room temperature for 3 hours, and turbidity appeared. After the reaction was monitored by TLC, a solid was obtained by suction filtration, and the solid was recrystallized with 50% ethanol aqueous solution to obtain 7.8 g of the target compound 1.1 with a yield of 80%.

[0036] Synthesis of 3-ethoxy-4-(2-fluorobenzyloxy)-5-bromobenzaldehyde (1.2)

[0037] Compound 1.1 (3.0g, 12.3mmol) and o-fluorobenzyl bromide (2.31g, 12.3mmol) were dissolved in DMF (5mL), and potassium carbonate (2.04g, 14.75mmol) was adde...

Embodiment 2

[0044] 4-(3,4-bis(2-fluorobenzyloxy)-5-bromobenzylamino)phenol (2)

[0045]

[0046] The synthetic route of compound 2 is as follows:

[0047]

[0048] The synthesis of compound 2.1 is as shown in compound 1.1, the difference is that the 3-ethoxyl-4-hydroxybenzaldehyde used in the process of synthesis 1.1 is replaced by 3,4-dihydroxybenzaldehyde; the synthesis of compound 2.2 is as in compound 1.2, the difference is that compound 1.1 is replaced by compound 2.1; the synthesis of compound 2 is as shown in compound 1, the difference is that compound 1.2 is replaced by compound 2.2.

[0049] 1 H NMR (400MHz, DMSO-d 6 ): δ8.43(s, 1H), 7.59-6.44(m, 10H), 6.53(d, 2H, J=8.4Hz), 6.45(d, 2H, J=8.4Hz), 5.66(t, 1H, J=6.0Hz), 5.20(s, 2H), 4.99(s, 2H), 4.15(d, 2H, J=6.0Hz).

[0050] HRMS (ESI) calcd for C 27 h 22 BrF 2 NO 3 [M+H] + 526.0829, found 526.0834.

Embodiment 3

[0052] 4-(3-Cyclohexamethyleneoxy-4-(2-fluorobenzyloxy)-5-bromobenzylamino)phenol (3)

[0053]

[0054] The synthetic route of compound 3 is as follows:

[0055]

[0056] Synthesis of Compound 3.1:

[0057] Compound 2.1 (300 mg, 1.39 mmol) was dissolved in DMF (3.0 mL), and sodium bicarbonate (174 mg, 2.07 mmol) and potassium iodide (69 mg, 0.414 mmol) were added, and o-fluorobenzyl bromide (519 mg, 2.76mmol), magnetically stirred, reacted overnight at 40°C, and followed the conversion of raw materials by TLC. The crude product was dissolved in water and extracted with ethyl acetate. Combined organic phases, anhydrous MgSO 4 Dry and concentrate. The product was separated by silica gel column chromatography (DCM / PE=9 / 1, v / v) to obtain 270 mg of the product as a white solid, with a yield of 60%.

[0058] The synthesis conditions of compound 3.2 are as the synthesis conditions of compound 1.2, and the difference is that two different reactants are used, namely compound...

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Abstract

The invention provides a benzyl-substituted aniline compound represented by a formula I shown in a drawing or pharmaceutically acceptable salts thereof, wherein R1 is independently selected from -COOH, -CONH2, H, -COOR5 (R5 is methyl or ethyl), -CN, -OH and -NH2COCH3, R2 and R3 are independently selected from C6-C10 aryl, C3-C6 cyclane and C1-C3 saturated alkyl or unsaturated alkyl respectively, and R4 is independently selected from -H, ethyl and acetyl. The compound and the pharmaceutically acceptable salts thereof, provided by the invention, can be used as farnesyltransferase inhibitors or can be used for preparing drugs for preventing or treating diseases related to farnesyltransferase, thereby having good medicine preparation prospects.

Description

technical field [0001] The invention relates to a benzyl-substituted aniline compound and its application. Background technique [0002] Post-translational modification (PTM) is of great significance to protein maturation, and these post-translational modifications include acetylation, alkylation, methylation and prenylation. Prenylation is catalyzed by farnesyltransferase. [0003] Farnesyltransferase (farnesyltransferase, FTase) is a zinc ion metalloenzyme capable of post-translational modification, which can catalyze the conversion of farnesyl (fifteen carbons) in farnesyl pyrophosphate (FPP). isoprenoid) to a tetrapeptide structure at the carbon-terminus of the Ras protein, this tetrapeptide structure is CAAX (C: cysteine, A: aliphatic amino acid, X: methionine, glutamic acid or alanine), and the farnesyl group is attached to the sulfur atom of cysteic acid. When the Ras protein is farnesylated, the fifteen-carbon isoprenoid connected to the carbon end increases the h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/58C07C213/00C07C213/02C07C255/63C07C253/30C07C229/60C07C227/10C07C227/18C07C233/43C07C233/25C07C231/02C07C231/12A61K31/137A61K31/277A61K31/245A61K31/196A61K31/167A61P35/00
Inventor 李洪林徐玉芳赵振江黄瑾杨柳清张媛赵雪梅寒冰栾国琴
Owner EAST CHINA UNIV OF SCI & TECH
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