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Condensed imidazolyl imidazoles as antiviral compounds

A compound and composition technology, applied in the direction of antiviral agents, compounds containing elements of group 3/13 of the periodic table, drug combinations, etc., can solve problems such as restricted use

Active Publication Date: 2016-05-25
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although drugs targeting the liver are widely used and have shown efficacy, toxicity and other side effects limit their use

Method used

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  • Condensed imidazolyl imidazoles as antiviral compounds
  • Condensed imidazolyl imidazoles as antiviral compounds
  • Condensed imidazolyl imidazoles as antiviral compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0241] In one embodiment, the present disclosure provides a compound, or a pharmaceutically acceptable salt or prodrug thereof, said compound having the general formula:

[0242]

[0243] Wherein the imidazole rings shown in the general formulas A1, A2, A3 and A4 are optionally substituted by one or more groups independently selected from halogen, haloalkyl, cyano or alkyl.

[0244] In one embodiment, the present disclosure provides a compound, or a pharmaceutically acceptable salt or prodrug thereof, said compound having the general formula:

[0245]

[0246] Wherein the imidazole rings shown in the general formulas A2 and A4 are optionally substituted by one or more groups independently selected from halogen, haloalkyl, cyano or alkyl.

[0247] In one embodiment, E 1a and E 1b At least one of is -N(H)(alkoxycarbonyl).

[0248] In one embodiment, E 1a and E 1b At least one of is -N(H)C(=O)OMe.

[0249] In one embodiment, E 1a and E 1bBoth are -N(H)C(=O)OMe.

[...

Embodiment LQ

[0302]

[0303]

[0304] 7-(2-Bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one

[0305] 7-Hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours, then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL), and the suspension was stirred for thirty minutes. 7-(2-Bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 89% yield) was isolated by filtration.

[0306] 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

[0307] To a solution containing palladium(II) pivalate (1.18g, 3.8mmol), tris(4-fluorophenyl)phosphine (1.20g, 3.8mmol), pivalic acid (2.33g, 22.8mmol) and potassium carbonate ( 31.8 g, 228 mmol) in a 1 L fla...

Embodiment L

[0322]

[0323] (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4-tricarboxylate

[0324] To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (9.0 g, 35.4 mmol) in MeOH (196 mL) was added HCl ( 4M in 1,4-dioxane, 100 mL, 403 mmol). The solution was stirred at room temperature for 16 h, and concentrated in vacuo. The crude intermediate was dissolved in EtOAc (180 mL) and basified with aqueous bicarbonate (sat.). Di-tert-butyl bicarbonate (8.5 g, 38.9 mmol) was added and the biphasic solution was stirred at room temperature for 12 h. The layers were then separated, and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, passed through Na 2 SO 4 Dried and concentrated. The crude oil was purified by silica gel chromatography (15% to 40% to 100% EtOAc / hexanes) to provide (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4 - Tricarboxylates (9.56 g, 94%).

[0325] (3S,5S)-1-(tert-butoxycarbon...

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Abstract

The present disclosure relates to antiviral compounds, compositions containing the compounds, and methods of treatment involving the administration of the compounds, as well as processes and intermediates for the preparation of the compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61 / 560,654, filed November 16, 2011, which is hereby incorporated by reference in its entirety. Background technique [0003] Hepatitis C is considered a chronic viral disease of the liver characterized by liver disease. Although drugs that target the liver are widely used and have shown efficacy, toxicity and other side effects have limited their use. Inhibitors of hepatitis C virus (HCV) are used to limit the establishment and progression of HCV infection and in diagnostic tests for HCV. [0004] There is a need for new HCV therapeutics. In particular, there is a need for HCV therapeutics that have broad inhibitory activity against HCV genotypes (eg, genotypes 1a, 1b, 2a, 3a, 4a). There is also a particular need for agents that are not prone to viral resistance. Resistance mutations to inhibitors of HCV NS5A of genotypes...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/052A61K31/4188
CPCC07D491/052A61K31/4188A61P31/12A61K31/7064A61K31/7072A61K47/60A61K38/06A61K38/07C07D405/12A61K45/06A61K31/7056A61K38/21A61P1/16A61P31/14A61P43/00A61K2300/00C07F5/025
Inventor 伊丽莎白·M·培根杰里米·J·科特雷耳艾希莉·安妮·卡塔娜达瑞尔·加藤埃文·S·雷戈夫斯基约翰·O·林科詹姆斯·泰勒庆 维也特·陈特里萨·亚历杭德拉·特雷霍 马丁杨正宇希拉·茨普费尔
Owner GILEAD SCI INC
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