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Novel inhibitors of hepatitis C virus

A technology with limited conditions and alkyl groups, applied in the field of inhibitor compounds, can solve problems such as reported side effects, long treatment process, and unmet urgent needs.

Inactive Publication Date: 2013-07-03
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although good cure rates have been reported, the course of treatment is lengthy and is accompanied by unwanted side effects
Therefore, there is an urgent unmet need in HCV treatment

Method used

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  • Novel inhibitors of hepatitis C virus
  • Novel inhibitors of hepatitis C virus
  • Novel inhibitors of hepatitis C virus

Examples

Experimental program
Comparison scheme
Effect test

example

[0307] The following synthetic examples and biological examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. In the following examples, the following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their accepted meanings.

[0308] ACN = acetonitrile

[0309] DCM = dichloromethane

[0310] DMA = N, N-dimethylacetamide

[0311] DMF = N,N-Dimethylformamide

[0312] DMSO = dimethyl sulfoxide

[0313] EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0314] EtOAc = ethyl acetate

[0315] h = hour

[0316] HATU = N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium salt of hexafluorophosphate

[0317] HCTU = 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate

[0318] HOAt = 1-hydroxy-7-azabenzotriazole

[0319] min = minute

[0320] Pd(dppf)Cl 2 = Dichloro(1,1'-bis(diphenylphosph...

example 1

[0669] Example 1: {(S)-1-[(S)-2-(4-{4'-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoylamino]-biphenyl -4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-methyl carbamate

[0670]

[0671] To a solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid (0.015 g, 0.055 mmol) in dichloromethane (2 mL, 30 mmol) was added N,N-dimethylformamide (0.004 mL, 0.055 mmol) and oxalyl chloride (0.014 mL, 0.164 mmol). The reaction mixture was stirred for 25 minutes, followed by the sequential addition of N,N-diisopropylethylamine (0.048 mL, 0.273 mmol) and ((S)-1-{(S)-2-[4-(4'-amino -biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-methyl carbamate (0.025 g, 0.055 mmol). The reaction mixture was stirred for 90 minutes, dried by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by preparative HPLC to afford the trifluoroacetate salt of the title compound (7.9 mg). (m / z): C 41 h 47 N 7 o 5 [M+H] of + The ...

example 2

[0672] Example 2: ((S)-1-{(S)-2-[4-(4'-{4-[4-(2,2-Dimethyl-propionyl)-piperazin-1-yl] -Benzoylamino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-methyl carbamate

[0673]

[0674] Stir 4-[4-(2,2-Dimethyl-propionyl)-piperazin-1-yl]-benzoic acid (10.3 mg, 0.036 mmol), N-(3-dimethylaminopropyl)- N'-Ethylcarbodiimide hydrochloride (8.17mg, 0.043mmol), 1-hydroxy-7-azabenzotriazole (6.77mg, 0.050mmol) in dichloromethane (0.3mL, 4mmol) The reaction mixture was dissolved and stirred for another 20 minutes. Then add ((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidin-1- Carbonyl}-2-methyl-propyl)-methyl carbamate (8.2 mg, 0.018 mmol) and N,N-diisopropylethylamine (7.43 μL, 0.0426 mmol). The reaction mixture was stirred overnight, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by preparative HPLC to afford the title compound as the trifluoroacetate salt (5.6 mg). (m / z): C 42 h 51 N 7 o 5 [M+H] of + The ...

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Abstract

The invention provides compounds of formula (I) wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.

Description

technical field [0001] The present invention relates to compounds useful as inhibitors of hepatitis C virus (HCV) replication. The present invention also relates to pharmaceutical compositions comprising said compounds, methods of using said compounds to treat HCV infection, and processes and intermediates suitable for preparing said compounds. Background technique [0002] A recent estimate of the number of people infected with hepatitis C virus (HCV) worldwide exceeds 170 million, including 3 million Americans. The infection rate is thought to be approximately 4 to 5 times that of the human immunodeficiency virus (HIV). While in some individuals the natural immune response is able to defeat the virus, in most cases chronic infection is established leading to an increased risk of developing cirrhosis and hepatocellular carcinoma. Thus, hepatitis C infection poses a serious public health problem. [0003] By mid-2011, the accepted standard of care for HCV involved the use...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/4025A61K31/12
CPCA61K31/496A61P1/16A61P31/14C07D401/14C07D403/14A61K45/06
Inventor 罗伯特·默里·麦金内尔丹尼尔·D·朗洛里·琼·范奥登姜岚曼迪·洛大介·罗兰·齐藤希拉·齐普费尔埃里克·L·施坦格兰卡萨德拉·莱帕科加文·奥加瓦黄晓军张伟江
Owner THERAVANCE BIOPHARMA R&D IP LLC
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