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Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication

a macrocyclic inhibitor and hepatitis c virus technology, applied in the direction of chemical treatment enzyme inactivation, drug composition, peptide, etc., can solve the problems of 40% to 50% of patients who fail therapy, non-responders or relapsers, patients currently have no effective therapeutic alternative, etc., to achieve the effect of increasing liver function

Inactive Publication Date: 2009-06-11
INTERMUNE INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0219]Preferred embodiments provide a method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound.

Problems solved by technology

Nevertheless, even with combination therapy using pegylated IFN-α plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders or relapsers.
These patients currently have no effective therapeutic alternative.
In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.
Since the risk of HCV-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965-1985.

Method used

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  • Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication
  • Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication
  • Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication

Examples

Experimental program
Comparison scheme
Effect test

example 13-1

[1012]

Step 1: Synthesis of tert-butyl 3-(((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1013]

[1014]To a flask charged with ethyl-(1R,2S)-1-amino-2-vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), 2-(tert-butoxycarbonyl)-6-(3-chlorophenoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.31 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were added 30 mL DMF to make a solution. It was cooled to 0° C. in an ice-water bath, followed by slow addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while stirring. The reaction was allowed to warm up to rt and stirred overnight.

[1015]After 16 h, the reaction was complete as monitored by HPLC. It was diluted with EtOAc (100 mL), washed with water (3×40 mL), sat. NaHCO3 (2×40 mL), and brine (2×40 mL), then dried over Na2SO4 and concentrated down to give a dark copper colored oil. The crude was purified on the Horizon Biotage instrument using a C-18 column (elue...

example 13-2

[1030]

[1031]Cyclopentyl (1aS,9S,17aR,19aR,Z)-15-(3-chlorophenoxy)-19a-(cyclopropylsulfonylcarbamoyl)-10,18-dioxo-1a,4,5,6,7,8,9,10,12,17,17a,18,19,19a-tetradecahydro-1H-11,14-diaza-bicyclo[13.1.0]hexadeca-1(15),2-dieno[11,12-b]isoquinolin-9-ylcarbamate (Compound 2005) was synthesized according to the procedure described in Example 13-1 and separated as a diasteriomer, (1 mg, 1%) MS m / e 752 (M−−H), using the following preparative HPLC conditions:[1032]Column: YMC ODS-AQ, 20×250 mm, 10-micron particle size, 120-angstrom pore size[1033]Mobile Phase Gradient: 5-95% B in 45 minutes[1034]A: water+0.01% HFBA+1% IPA[1035]B: MeCN+0.01% HFBA+1% IPA[1036]Flow rate: 15 ml / min[1037]Temperature: 25° C.[1038]Wavelength: 220 nm

example 13-3

[1039]

[1040]Cyclopentyl (1aS,9S,17aS,19aR,Z)-15-(3-chlorophenoxy)-19a-(cyclopropylsulfonylcarbamoyl)-10,18-dioxo-1a,4,5,6,7,8,9,10,12,17,17a,18,19,19a-tetradecahydro-1H-11,14-diaza-bicyclo[13.1.0]hexadeca-1(15),2-dieno[11,12-b]isoquinolin-9-ylcarbamate (Compound 2005) was synthesized according to the procedure described in Example 13-1 and separated as a diasteriomer, (5 mg, 4%) MS m / e 752 (M−H), using the following preparative HPLC conditions:[1041]Column: YMC ODS-AQ, 20×250 mm, 10-micron particle size, 120-angstrom pore size[1042]Mobile Phase Gradient: 5-95% B in 45 minutes[1043]A: Water+0.01% HFBA+1% IPA[1044]B: MeCN+0.01% HFBA+1% IPA[1045]Flow rate: 15 ml / min[1046]Temperature: 25° C.[1047]Wavelength: 220 nm

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Abstract

The embodiments provide compounds of the general Formulae (I) through general Formula (VIII), as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.[0003]2. Description of the Related Art[0004]Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.[0005...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/21C07K5/12A61K38/12C07D209/18C12N9/99A61K39/395
CPCA61K38/00A61K38/212A61K38/217A61K38/55C07D471/04C07D487/04C07K5/0804C07K5/0806A61K38/1793A61K38/2292A61P1/16A61P31/12A61P31/14A61P43/00Y02A50/30A61K2300/00A61K31/407
Inventor BLATT, LAWRENCE M.SEIWERT, SCOTT D.ANDREWS, STEVEN W.MARTIN, PIERRESCHUMACHER, ANDREASBARNETT, BRADLEYEARY, C. TODDKAUS, ROBERTKERCHER, TIMOTHYLIU, WEIDONGLYON, MICHAELNICHOLS, PAULWANG, BINSAMMAKIA, TAREKKENNEDY, APRILJIANG, YUTONG
Owner INTERMUNE INC
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