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Oligonucleotide analogs, their preparation and use

  • US 6,033,909 A
  • Filed: 07/27/1994
  • Issued: 03/07/2000
  • Est. Priority Date: 01/22/1992
  • Status: Expired due to Term
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Assignment
First Claim
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1. An oligonucleotide analog of the formula I ##STR35## wherein:

  • R1 is hydrogen, C1 -C18 -alkyl, C2 -C18 -alkenyl, C2 -C18 -alkynyl, C2 -C18 -alkylcarbonyl, C3 -C19 -alkenylcarbonyl, C3 -C19 -alkynylcarbonyl, C6 -C20 -aryl, (C6 -C14)-aryl-(C1 -C8 -alkyl), or a radical of the formula II ##STR36## R2 is hydrogen, hydroxyl, C1 -C18 -alkoxy, halogen, azido or NH2 ;

    B is a conventional base in nucleotide chemistry;

    a is oxy or methylene;

    n is a number from 1 to 100;

    W is oxo, thioxo or selenoxo;

    V is oxy, thio, or imino;

    Y is oxy, thio, imino or methylene;

    Y'"'"' is oxy, thio, imino or (CH2)m or V(CH2)m ;

    m is a number from 1 to 18;

    X is hydroxyl or mercapto;

    U is hydroxyl, mercapto, SeH, C1 -C18 -alkoxy, C1 -C18 -alkyl, C6 -C20 -aryl, (C6 -C14)-aryl-(C1 -C8)-alkyl, NHR3, NR3 R4 or a radical of the formula III
    

    space="preserve" listing-type="equation">(OCH.sub.2 CH.sub.2).sub.p O(CH.sub.2).sub.q CH.sub.2 R.sup.11(III)R3 is C1 -C18 -alkyl, C6 -C20 -aryl, (C6 -C14)-aryl-(C1 -C8)-alkyl or 2-(CH2)c -[NH(CH2)c]d -NR12 R12 ;

    c is a number from 2 to 6;

    d is a number from 0 to 6;

    R12 is independently hydrogen, C1 -C6 -alkyl or C1 ∝

    C4 -alkoxy-C1 -C6 -alkyl;

    R4 is C1 -C18 -alkyl, C6 -C20 -aryl or (C6 -C10)-aryl-(C1 -C8)-alkyl, or in the case of NR3 R4 is, together with R3 and the nitrogen atom carrying them, a 5-6-membered heterocyclic ring, which can additionally contain a further hetero atom selected from the group comprising O, S and N;

    p is a number from 1 to 100;

    q is a number from 0 to 22;

    R11 is hydrogen or a functional group;

    Z=Z'"'"' are hydroxyl;

     mercapto;

     SeH;

     C1 -C22 -alkoxy;

     --O--(CH2)b -NR12 R13, where b is a number from 1 to 6, and R13 is C1 -C6 -alkyl, or R12 and R13 together with the nitrogen atom carrying them form a 3-6-membered ring;

    C1 -C18 -alkyl;

     C6 -C20 -aryl;

     (C6 -C14)-aryl-(C1 -C8)-alkyl;

     (C6 -C14)-aryl-(C1 -C8)-alkoxy, where aryl is optionally substituted by 1, 2 or 3 identical or different radicals selected from the group comprising carboxyl, amino, nitro, C1 -C4 -alkylamino, C1 -C6 -alkoxy, hydroxyl, halogen and cyano;

    C1 -C18 -alkyl-mercapto;

     NHR3 ;

     NR3 R4 ;

     a radical of the formula III;

     or a group which favors intracellular uptake with the proviso that heteroaryl moieties containing 1 or 2 nitrogen atoms are excluded, or serves as the label for a DNA probe, or, during hybridization of the oligonucleotide analog to the target nucleic acid, attacks the latter with binding, crosslinking or cleavage, with the proviso that Z includes no functional moieties arising through cleavage of Z from a support;

     the curved bracket indicates that R2 and the neighboring phosphoryl residue can be located in the 2'"'"'- and 3'"'"'-position or else the opposite way round in the 3'"'"'- and 2'"'"'-position, where each nucleotide can be present in its D- or L-configuration and the base B can be located in the α

    - or β

    -position, with the proviso that, if Z is hydroxyl, mercapto, methyl or ethoxy, at least one of the groups X, Y, Y'"'"', V and W is not hydroxyl, oxy or oxo, or R1 is not hydrogen or methylphosphonate monoester;

    or a physiologically tolerable salt thereof.

      

    

  

  
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