Macrocyclic compounds as inhibitors of viral replication

A compound, cycloalkyl technology, used in antiviral agents, drug combinations, organic chemistry, etc., to solve problems such as non-response, patients without treatment options, and patient treatment failures

Inactive Publication Date: 2007-03-28
INTERMUNE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, even with combination therapy of pegylated IFN-α and ribavirin, 40% to 50% of patients fail trea

Method used

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  • Macrocyclic compounds as inhibitors of viral replication
  • Macrocyclic compounds as inhibitors of viral replication
  • Macrocyclic compounds as inhibitors of viral replication

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[1020] Preparation of Part A Virus Inhibitors

[1021] Compounds of general formula I can be synthesized in the same general manner as described below for compounds of general formula II-XIX. The synthesis of various specific compounds of general formula I is described in the examples below. Variations in sequence will be appreciated by those skilled in the art and will further appreciate the importance of appropriate reaction conditions for similar reactions shown or otherwise known that may be suitably used in the processes described hereinafter for the preparation of compounds of formula I. Variety.

[1022] The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography and the like.

[1023] Salts of compounds of the above formulas are prepared by reacting an appropriate base or acid with a stoichiometric equivalent of a compound of formula I.

[1024] Preparation of Part B Virus Inhibitors

[1025...

example 1-1

[1030] Example 1-1: Synthesis of Compound #101 (Compound AR00220042) by Method A:

[1031]

[1032] Compound #101 (Compound AR00220042)

[1033] Method A:

[1034]

[1035] Step 1: Synthesis of tert-butyl 2S-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy-pyrrolidine-1-carboxylate (3)

[1036]

[1037] Add ethyl-(1R, 2S) / (1S, 2R)-1-amino-2-vinylcyclopropylcarboxylate (1, 1.0g, 5.2mmol), trans-N-(tert-butyl A solution was made by adding 30 mL of DMF to a flask of oxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 eq) and HATU (2.7 g, 1.1 eq). The solution was cooled to 0°C in an ice-water bath, then a solution of DIEA (4.4ml, 4eq) in DMF (15ml) was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight.

[1038] After 16 h, the reaction was monitored for completion by HPLC. Diluted with EtOAc (100 mL), water (3×40 mL), saturated sodium bicarbonate (NaHCO 3 (2×40mL)) and brine (2×40mL), followed by Na 2 ...

example 1-2

[1059] Example 1-2: Synthesis of Compound #101 (Compound AR00220042) by Method B:

[1060] Method B:

[1061]

[1062] Compound #101 was also prepared according to the above procedure. The synthesis of macrocyclic intermediate 10 described herein is analogous to that described in International Application PCT / CA00 / 00353 (publication No. WO 00 / 59929).

[1063] Step 1: Synthesis of tert-butyl 2S-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy-pyrrolidine-1-carboxylate (3)

[1064]

[1065] Add ethyl-(1R, 2S) / (1S, 2R)-1-amino-2-vinylcyclopropylcarboxylate (1, 1.0g, 5.2mmol), trans-N-(tert-butyl A solution was made by adding 30 mL of DMF to a flask of oxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 eq) and HATU (2.7 g, 1.1 eq). The solution was cooled to 0°C in an ice-water bath, then a solution of DIEA (4.4ml, 4eq) in DMF (15ml) was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight.

[1066] After 16 h...

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Abstract

The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including 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

[0001] cross-related applications [0002] This application is a continuation-in-part of U.S. Patent Application Serial No. 11 / 064,445, filed February 23, 2005, which is a continuation-in-part of PCT / US04 / 33970, filed October 13, 2004 PCT / US04 / 33970, claiming priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 60 / 511,541, filed October 14, 2003; U.S. Provisional Application No. 60 / 612,381 filed on April 22, U.S. Provisional Application No. 60 / 562,418 filed on April 14, 2004, and U.S. Provisional Application No. 60 / 558,161 filed on March 30, 2004 ; these applications are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to compounds, methods for their synthesis, pharmaceutical compositions and methods of treating flavivirus infections such as hepatitis C virus (HCV) infection. In detail, the present invention provides novel peptide analogs, pharmaceutical compositions containing these analogs and method...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07K5/08A61K31/495A61P31/12A61P1/16C07D245/00C07D209/00
Inventor 劳伦斯·M·布拉特史蒂文·M·温洛斯凯史蒂文·W·安德鲁斯凯文·R·孔德罗斯基江郁桐阿普里尔·L·肯尼迪乔治·A·多尔蒂约翰·A·乔西彼得·J·施滕格尔本杰明·T·伍达德马钱德·R·马杜鲁
Owner INTERMUNE INC
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