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Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

A technology of medicinal salts and compounds, applied in the field of 2' and/or 3' prodrugs, which can solve problems such as large side effects

Inactive Publication Date: 2008-05-07
INDENIX PHARM LLC +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as with monotherapy, in combination therapy, considerable side effects occur, including hemolysis, influenza-like symptoms, anemia, and fatigue (GaryL. Davis. Gastroenterology 118:S104-S114, 2000)

Method used

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  • Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
  • Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
  • Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

Examples

Experimental program
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example

[0744] Non-limiting examples include:

[0745] 1) Protease inhibitors

[0746] Examples include substrate-based NS3 protease inhibitors (Attwood et al, Antiviral peptide derivatives (antiviral peptide derivatives), PCT WO 98 / 22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al. ., Preparation and use of amino acid derivatives as anti-viralagents (preparation and use as an amino acid derivative of an antiviral agent), German Patent Publication No. DE 19914474; Tunget al., Inhibitiors of serine proteases, particularly hepatitis C virus NS3 proteases (inhibitors of serine proteases, especially hepatitis C virus NS3 protease), PCT WO 98 / 17679), including α-ketoamides and hydrazinoureas, and terminating electrophiles such as boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues (hepatitis C virus inhibitor peptide analogs), PCT WO 99 / 07734); non-substrate-based NS3 protease inhibitors such as 2,4,6-t...

Embodiment 1

[0856] Example 1: Preparation of 1′-C-methyl riboadenine by 6-amino-9-(1-deoxy-β-D-psicofuranosyl) purine

[0857] Melting points were determined on a Mel-temp II apparatus and are uncorrected. On a Bruker 400 AMX spectrometer, a 400 MHz 1 H NMR and 100MHz 13 C NMR, NMR spectra were recorded with TMS as internal standard. Chemical shifts (δ) are expressed in parts per million (ppm) and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). Infrared (IR) spectra were measured on a Nicolet 510P Fourier transform infrared (FT-IR) spectrometer. Mass spectra were recorded on a Micromass Autospec high resolution mass spectrometer. Thin layer chromatography (TLC) analyzes were performed on Uniplates (silica gel) from Analtech Co. Flash column chromatography was performed using silica gel-60 (220-440 mesh) or vacuum flash chromatography using silica gel G (TLC grade, >440 mesh). Ultraviolet (UV) spectra were obtained b...

Embodiment 2

[0880] Example 2: Preparation of 2'-C-methylribose-8-methyladenine

[0881] The target compound can be obtained according to the published method (R.E.Harry-O'kuru, J.M.Smith, and M.S.Wolfe, "A short, flexible route toward 2'-C-branched ribonucleosides", J.Org.Chem.1997, 62 , 1754-1759) prepared. (Process 9).

[0882] Process 9

[0883]

[0884] (a) Dess-Martin periodinane; (b) MeMgBr / TiCl 4 ; (c) BzCl, DMAP, Et 3 N; (d) bis(trimethylsilyl)acetamide, N 6 - Benzoyl adenine, TMSOTf; (e)NH 3 / MeOH

[0885]The 3'-prodrug of the 2'-branched nucleoside can be prepared according to the published method (Syntetic Communications, 1978, 8(5), 327-333; J.Am.Chem.Soc., 1999, 121(24) , 5661-5664) preparation. Alternatively, the 2'-branched nucleosides can be esterified without protection (Scheme 9b). Carbonyldiimidazole (377 mg, 2.33 mmol) was added to 15 ml of a solution of N-(tert-butoxycarbonyl)-L-valine (507 mg, 2.33 mmol) in anhydrous THF. The mixture was stirred at 20°C ...

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Abstract

2' and / or 3'-prodrugs of 1', 2', 3' or 4'-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are used in the prophylaxis and treatment of Flaviviridae infections, including HCV infections, and other related conditions. Compounds and compositions of the prodrugs of the invention are described. Also provided are methods and uses comprising administering an effective amount of a prodrug of the invention, or a pharmaceutically acceptable salt or derivative thereof. These agents are optionally administered in combination or alternately with other antiviral agents to prevent or treat flavivirus infection and other related conditions.

Description

[0001] This application is a divisional application of the Chinese patent application 03820501.7 submitted on June 27, 2003, and the invention title is "Modified 2' and 3'-nucleoside prodrugs for the treatment of flavivirus infection". [0002] Cross References to Related Applications [0003] This application claims U.S. Provisional Application No. 60 / 392,350, filed June 28, 2002; U.S. Provisional Application No. 60 / 466,194, filed April 28, 2003; and U.S. Provisional Application No. 60 / 470,949, the disclosure of each of which is hereby incorporated by reference. field of invention [0004] The present invention relates to the field of medicinal chemistry, in particular, to 6-modified 1', 2', 3' or 4'-branched pyrimidine nucleosides or 8- 2' and / or 3' prodrugs of modified 1', 2', 3' or 4'-branched purine nucleosides. Background of the invention [0005] Flaviviridae [0006] The Flaviviridae family of viruses comprises at least three separate genera: pestiviruses, which c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H19/10C07H19/16C07H19/20C07H19/04C07H19/044C07H19/048C07H19/052C07H19/056C07H19/12C07H19/14C07H19/22C07H19/23A61K31/7052A61K31/706A61P31/14
CPCY02A50/30
Inventor 让-皮埃尔·索马多西波罗·拉科拉理查德·斯托勒吉勒·戈瑟兰
Owner INDENIX PHARM LLC
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