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Compounds and methods for the treatment or prevention of flaviviridae viral infections

A compound and composition technology, applied in the field of ER and D, can solve problems such as hindering therapy compliance, failing to provide sustained viral response, and reducing doses

Inactive Publication Date: 2013-06-12
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This treatment does not provide a sustained viral response (SVR) in most patients infected with the most prevalent genotypes (1a and 1b)
In addition, significant side effects prevent compliance with current therapies and may require dose reduction or discontinuation in some patients

Method used

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  • Compounds and methods for the treatment or prevention of flaviviridae viral infections
  • Compounds and methods for the treatment or prevention of flaviviridae viral infections
  • Compounds and methods for the treatment or prevention of flaviviridae viral infections

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] Embodiment 1: the synthesis of compound of the present invention

[0209] Compounds of the invention described herein may be prepared by any suitable method known in the art, eg US6,881,741, US2005 / 0009804, US2006 / 0276533, WO2002 / 100851 and WO08 / 58393. The preparation of some typical compounds is described in detail below. The synthesis of some typical compounds of the invention is described below. In general, the compounds of the invention may be prepared by synthetic methods as those optionally with any desired suitable modifications.

[0210] A. General Analytical Methods

[0211] As used herein, the term RT(min) refers to the LCMS retention time in minutes associated with a compound. Unless otherwise indicated, the method used to obtain the reported retention times is as follows:

[0212] Column: YMC-Pack Pro C18, 50mm×4.6mm id

[0213] Gradient: 10-95% methanol / H 2 O. Flow rate: 1.5ml / min. UV-vis detection.

[0214] B. General Analytical and Synthetic Meth...

Embodiment 1B

[0395] Preparation of compound 3

[0396] Compound 3 was prepared by the general method in the general scheme below.

[0397] MS: m / z (obs.): 460.6 [M+H] + ;Rt=6.05min

[0398] 1 H NMR (300MHz,MeOD)δ6.99(s,1H),4.39(dd,J=15.9,7.6Hz,1H),2.75(dd,J=13.4,6.7Hz,1H),2.05-1.84(m, 4H),1.56(ddd,J=18.4,12.9,10.4Hz,10H),1.32(ddd,J=14.5,11.3,4.8Hz,8H),1.13-0.85(m,5H),0.76(t,J= 21.8Hz, 5H).

[0399] general plan

[0400]

[0401] step 1

[0402] To 5-iodo-3-[(1,4-dioxaspiro[4.5]dec-8-yl)-(4-trans-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid methyl ester ( 1 mmol) in DMF (10-20 mL) was added Et 3 N(1mmol),CuI(0.1-0.25mol%),tris(dibenzylideneacetone)dipalladium(0)(Pd 2 (dba) 3 ) (0.01-0.05mol%) and 2-substituted but-1-yne (1mmol). The mixture was heated at 60 °C overnight, then diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ), and then concentrate. The product was purified by silica gel chromatography (10-90% EtOAc in hexanes) to affo...

Embodiment 2

[0977] Embodiment 2: HCV replicon test

[0978] A. Principle

[0979] The following method describes the HCV replicon assay using the Huh7 hepatoma cell line (genotype 1b) (hereinafter referred to as cell line ET) containing a highly cell culture-adapted replicon. ET cells contain a highly cell culture-adapted replicon I 389 luc-ubi-neo / NS3-3' / 5.1 construct, which carries an intact copy of the firefly luciferase gene in addition to the neomycin gene (Krieger, N; Lohmann, V; Bartenschlager, R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J. Virol. 2001, 75, 4614-4624). A replicon cell line W11.8 containing the HCV1a genotype was also used. These two cell lines (genotype 1b and 1a) were able to measure RNA replication and translation by measuring luciferase activity (for genotype 1b) or by measuring NS5A levels (for genotype 1a) using an ELISA assay. It has been demonstrated that luciferase activity closely follows replicon RNA levels ...

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Abstract

A compound is selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof.

Description

[0001] Inventors: Jeremy Green, Laval Chan Chun Kong, Sanjoy Kumar Das, Carl Poisson, Suganthini Nanthakumar, Nathan Waal, Pan Li, Steven Ronkin, David J. Lauffer and Dean M. Wilson [0002] Attorney No.: VPI / 10-128WO [0003] related application [0004] This application claims the benefit of U.S. Provisional Application No. U.S.S.N. 61 / 374,396, filed August 17, 2010. The entire teachings of this application are incorporated herein by reference. Background of the invention [0005] Hepatitis C virus (HCV) is a positive-sense RNA virus belonging to the Flaviviridae family and is closely related to pestiviruses including hog cholera virus and bovine viral diarrhea virus (BVDV). HCV is thought to replicate by producing a complementary negative-strand RNA template. Since there is no efficient culture replication system for this virus, HCV particles were isolated from pooled human plasma and were shown to have a diameter of approximately 50-60 nm by electron microscopy. The HC...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38A61K31/381A61P31/12C07D409/12C07D333/40C07D409/06C07D413/12C07D417/12
CPCA61K31/381C07D333/38C07D333/40C07D409/06C07D409/12C07D413/12C07D417/12A61P1/16A61P31/12A61P31/14A61P43/00A61K31/422A61K31/4245A61K31/427A61K31/4436A61K31/4535A61K31/497A61K31/5377A61K31/7056A61K38/212
Inventor J·格林L·C·C·孔S·K·达斯C·普瓦松S·南萨库马尔N·瓦尔李磐S·罗恩金D·J·劳费尔D·M·威尔逊
Owner VERTEX PHARMA INC
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