Aniline compound as farnesyltransferase inhibitor and application thereof

A technology of aniline compounds and farnesyltransferase, which is applied in the field of aniline compounds, can solve problems such as uncontrolled cell proliferation and achieve good drug prospects

Active Publication Date: 2015-05-27
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Mutation of Ras protein keeps Ras protein in a state of continuous activation, cell proliferation is out of control, leading to tumor formation

Method used

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  • Aniline compound as farnesyltransferase inhibitor and application thereof
  • Aniline compound as farnesyltransferase inhibitor and application thereof
  • Aniline compound as farnesyltransferase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 3-Phenyl-4-(4-(4-fluorophenoxy)anilinoyl)-butyric acid (1)

[0031]

[0032] Synthesis of 4-(4-fluorophenoxy)aniline (1.4)

[0033]

[0034] p-Fluoronitrobenzene (705 mg, 5.0 mmol), p-fluorophenol (560 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were dissolved in DMF (5 mL). The reaction was warmed to 70°C and stirred overnight. After the reaction was monitored by TLC, the reaction solution was dissolved in ethyl acetate, extracted with water and brine, the organic phase was separated and dried with anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain 990 mg of light yellow product 1.3, with a yield of 85%.

[0035] 1 H NMR (400MHz, DMSO-d 6 ): δ8.26(d, 2H, J=8.8Hz), 7.37-7.11(m, 4H), 7.12(d, 2H, J=9.2Hz).

[0036] SnCl 2 ·H 2 O (2.25g, 10mmol) was dissolved in concentrated hydrochloric acid (10mL), then compound 1.3 was added into the mixture (249mg, 1mmol), and the reaction solution was heated to refl...

Embodiment 2

[0049] 3-Phenyl-4-(4-(4-methoxyphenoxy)anicarboyl)-butyric acid (2)

[0050]

[0051] For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-methoxyphenol, and the product was a white solid with a yield of 61%.

[0052] 1 H NMR (400MHz, DMSO-d 6 ): δ12.05(s, 1H), 9.82(s, 1H), 7.47(d, 2H, J=8.8Hz), 7.29-7.27(m, 4H), 7.21-7.15(m, 1H), 6.93( s, 4H), 6.85 (d, 2H, 9.2Hz), 3.72-3.53 (m, 1H), 2.71-2.54 (m, 4H).

[0053] 13 C NMR (100MHz, DMSO-d 6 ): δ173.3, 169.6, 155.8, 153.6, 150.7, 144.1, 134.7, 128.7, 127.9, 126.8, 121.3, 120.4, 118.4, 115.5, 55.9, 43.2, 40.6, 38.7.

[0054] HRMS (ESI) calcd for C 24 h 22 NO 5 [M-H] + 404.1498, found 404.1502.

Embodiment 3

[0056] 3-Phenyl-4-(4-(3,4-dichlorophenoxy)phenylcarbamoyl)-butanoic acid (3)

[0057]

[0058] For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with 3,4-dichlorophenol, and the product was a white solid with a yield of 45%.

[0059] 1 H NMR (400MHz, DMSO-d 6 ): δ12.07(s, 1H), 9.95(s, 1H), 7.60-7.56(m, 3H), 7.30-7.29(m, 4H), 7.21-7.19(m, 2H), 7.03(d, 2H , J=8.8Hz), 6.94(d, 1H, J=8.4Hz), 3.65-3.55(m, 1H), 2.73-2.55(m, 4H).

[0060] 13 C NMR (100MHz, DMSO-d 6 ): δ173.3, 169.8, 157.7, 150.8, 144.0, 136.4, 132.4, 131.9, 128.7, 127.9, 126.9, 125.2, 121.3, 120.5, 119.8, 118.3, 43.2, 38.7.

[0061] HRMS (ESI) calcd for C 23 h 20 ClNO 4 [M+H] + 444.0769, found 444.0778.

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Abstract

The invention provides an aniline compound represented by a formula I shown in a drawing or pharmaceutically acceptable salts thereof, wherein X is independently selected from COOH and SO2NH2, R1 and R2 are independently selected from H, C1-C3alkyl or alkoxy, CF3, F, Cl, Br, I, NH2 and NO2 respectively, m and n are respectively integers of 0-5, and y is 0 or 1. 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 an aniline compound as a farnesyl transferase inhibitor 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/29C07C231/02C07C311/13C07C311/27C07C303/36A61K31/192A61K31/18A61P35/00
Inventor 徐玉芳李洪林赵振江黄瑾杨柳清陈甜甜赵雪梅寒冰张媛
Owner EAST CHINA UNIV OF SCI & TECH
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