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Macrocyclic Inhibitors of Flaviviridae Viruses

A technology of spiro rings and compounds, applied in the field of macrocyclic inhibitors of Flaviviridae viruses

Inactive Publication Date: 2018-03-23
GILEAD SCI INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of sanglifehrin or its derivatives have been used in human antiviral therapy

Method used

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  • Macrocyclic Inhibitors of Flaviviridae Viruses
  • Macrocyclic Inhibitors of Flaviviridae Viruses
  • Macrocyclic Inhibitors of Flaviviridae Viruses

Examples

Experimental program
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preparation example Construction

[0260] Preparation of macrocycles

[0261] Compounds of the invention, such as those of general formula (I) and (II), can be prepared according to the schemes described below, but it will be appreciated that modifications of the illustrated methods or other methods can also be used. As illustrated in Scheme 1, from the five key components A-E, through the appropriate use of protecting groups (PG) by those skilled in the art 1 -PG 8 ), and combine them in order to synthesize the macrocyclic compound M (Q is NH). The dashed lines numbered 1-5, referred to herein as connection 1, connection 2, etc. respectively, are the 5 connections used to bind components A-E. The order in which a particular linkage occurs can vary and depends on the choice of protecting group and the desired chemistry. Typically, ligation 3, 4 or 5 is used as the final macrocyclization step.

[0262] plan 1

[0263]

[0264] Linkages 1, 2 and 3 are amide bonds. Linkages are formed between representati...

Embodiment 1 to 20

[0365] For Examples 1 to 20, unless otherwise noted, preparative HPLC was performed on a Gilson HPLC system using an Agilent Eclipse XDB / C187micron, 250 x 21.2 mm semi-preparative column and an acetonitrile / water mobile phase at a flow rate of 20 mL / min.

[0366] For Examples 121 to 175, unless otherwise noted, preparative HPLC was performed on a Shimadzu HPLC system using a 21.2 x 250 mm 10 micro C18 Phenomenex Gemini semi-preparative column and an acetonitrile / water mobile phase at a flow rate of 20 mL / min.

[0367] List of Abbreviations and Acronyms

[0368] Abbreviation Meaning

[0369] ℃ degrees Celsius

[0370] di-tBuXPhos 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-bis

[0371] benzene

[0372] 2,6-lut. 2,6-lutidine

[0373] MNBA 2-methyl-6-nitrobenzoic anhydride

[0374] 4AMS 4 angstrom molecular sieve

[0375] Acetyl

[0376] ACN acetonitrile

[0377] app obvious

[0378] Aq water content

[0379] BINAP (2,2'-bis(biphenylphosphino...

Embodiment 1

[0503] Example 1: (E)-(2R,5S,11S,14S,17R,18R)-18-hydroxy-14-isopropyl-2,11,17-trimethyl-3,9,12,15, 28-Pentaza-tricyclo[21.3.1.1*5,9*]octadeca-1(26),21,23(27),24-tetraen-4,10,13,16-tetraone : Compound 1

[0504]

[0505] Preparation of 1-((1R,5S)-10,10-dimethyl-3,3-dioxo-3λ*6*-thio-4-aza-tricyclo[5.2.1.0* in toluene (50 mL) A solution of 1,5*]dec-4-yl)-propan-1-one (3.95 g, 14.55 mmol) was then evaporated to dryness. This process was repeated, and the resulting white solid was dissolved in anhydrous dichloromethane (16 mL). A small amount of calcium hydride was added, followed by tert-butyldimethylsilyl trifluoromethanesulfonate (3.83 mL, 14.5 mmol) and anhydrous triethylamine (2.33 mL, 16.7 mmol). The reaction mixture was stirred at RT ("RT") for 15 hours ("h") under a nitrogen atmosphere. The resulting solution was evaporated to give a thick paste which was redissolved in anhydrous dichloromethane (15 mL) and added dropwise to anhydrous dichloromethane (20 mL ) in a s...

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Abstract

The present invention provides a compound of general formula I: and pharmaceutically acceptable salts and esters thereof. The provided compounds, compositions and methods are useful in the treatment of viral infections, particularly hepatitis C infections.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. §119(e) of US Provisional Application Serial No. 61 / 657,562, filed June 8, 2012, which is hereby incorporated by reference in its entirety. technical field [0003] The application provides novel compounds that inhibit viruses, compositions containing such compounds, and methods of treatment involving the administration of such compounds. Background technique [0004] RNA viruses comprising the family Flaviviridae comprise at least three distinguishable genera, including pestiviruses, flaviviruses and hepaciviruses (Calisher et al., J. Gen. Virol. 1993, 70, 37-43). Although pestisviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, hog cholera) and sheep border disease (BDV), their importance in human disease Few have been adequately characterized (Moennig, V. et al., Adv. Vir. Res. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/18C07D498/18A61K31/504A61P31/12A61P35/00
CPCC07D487/18C07D498/18A61K38/21A61K38/12C07K5/06052A61P1/16A61P11/00A61P29/00A61P3/04A61P31/00A61P31/12A61P31/14A61P31/18A61P35/00A61P37/02A61P43/00Y02A50/30A61K31/504A61K45/06C07K5/06086C07K5/06139C07K5/06191
Inventor 卡洛琳·阿西罗维多利亚 亚历山德拉·斯特德曼西蒙 尼尔·佩蒂特卡琳 G.·波尔伦尼克利诺斯·拉扎里迪斯大卫 肯尼斯·迪安尼尔 安德鲁·邓巴艾德里安 约翰·海顿安德鲁 约翰·基茨达斯汀 斯科特·西格尔卡皮尔 库马尔·卡尔基亚当 詹姆斯·施里尔彼得·扬萨理查德·麦肯曼简 伊夫斯·齐瓦
Owner GILEAD SCI INC
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