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2'-Fluoronucleoside phosphonates as antiviral agents

  • US 20070225249A1
  • Filed: 03/22/2007
  • Published: 09/27/2007
  • Est. Priority Date: 03/23/2006
  • Status: Active Grant
First Claim
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1. A compound having the formula (I) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

  • a) X is O, S, SO2, or CH2;

    b) Z is O, S, or NH;

    c) n is 1 or 2;

    d) R1 is H or CH3;

    e) R2 and R3 are independently a hydrogen, halogen (F, Cl, Br, I), OH, OR′

    , SH, SR′

    , N3, NH2, NHR′

    , CN, OCOR′

    , OCOOR′

    , lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH═

    CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH═

    CHCl, CH═

    CHBr and CH═

    CHI, lower alkynyl of C2-C6 such as C≡

    CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, lower alkyl acid of C2-C6 such as CH2COOH and CH2CH2COOH, lower alkyl acid ester of C2-C6 such as CH2COOR′ and

    CH2CH2COOR′

    ;

    f) R4 and R5 are independently a hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding OH group. The term “

    preferentially removed in a hepatocyte”

    as used herein means at least part of the group is removed in a hepatocyte at a rate higher than the rate of removal of the same group in a non-hepatocytic cell (e.g., fibroblast or lymphocyte). It is therefore contemplated that the removable group includes all pharmaceutically acceptable groups that can be removed by a reductase, esterase, cytochrome P450 or any other specific liver enzyme. Alternative contemplated groups may also include groups that are not necessarily preferentially removed in a hepatocyte, but effect at least some accumulation and/or specific delivery to a hepatocyte (e.g., esters with selected amino acids, including valine, leucine, isoleucine, or polyarginine or polyaspartate);

    g) Base is a heterocycle containing at least one nitrogen,

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