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Modified oligonucleotides, their preparation and their use

  • US 6,066,720 A
  • Filed: 06/10/1998
  • Issued: 05/23/2000
  • Est. Priority Date: 05/02/1994
  • Status: Expired due to Term
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Petitions
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Forward Citations
3
Assignments
First Claim
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1. An oligonucleotide of the formula I ##STR17## and the physiologically tolerated salts thereof, in which R1 is hydrogen, C1 -C18 -alkyl, C2 -C18 -alkenyl, C2 -C18 -alkynyl, C2 -C18 -alkylcarbonyl, C3 -C19 -alkenylcarbonyl, C3 -C19 -alkynylcarbonyl, (C6 -C14)-aryl-(C1 -C8)-alkyl, a protective group which is customary in nucleotide chemistry, or a radical of the formula IIa ##STR18## R1a is hydrogen, C1 -C18 -alkyl, C2 -C18 -alkenyl, C2 -C18 -alkynyl, C2 -C18 -alkylcarbonyl, C3 -C19 -alkenylcarbonyl, C3 -C19 -alkynylcarbonyl, (C6 -C14)-aryl-(C1 -C8)-alkyl, or a radical of the formula IIb ##STR19## R2 is hydrogen, hydroxyl, C1 -C18 -alkoxy, C1 -C6 -alkenyloxy, halogen, azido or NH2 ;

  • a is oxy or methylene;

    n is an integer from 3 to 99;

    W is oxo, thioxo or selenoxo;

    V is oxy, sulfanediyl or imino;

    Y is oxy, sulfanediyl, imino or methylene;

    Y'"'"' is oxy, sulfanediyl, imino, (CH2)m or V(CH2)m'"'"' in whichm is an integer 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.sub.5(III)in whichR3 is C1 -C18 -alkyl, C6 -C20 -aryl, (C6 -C14)-aryl-(C1 -C8)-alkyl, or 2-(CH2)c -(NH(CH2)c)d --NR6 R6, in which c is an integer from 2 to 6 and d is an integer from 0 to 6, and R6 are, independently of each other, hydrogen or 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 heteroatom selected from O, S and N,p is an integer from 1 to 100,q is an integer from 0 to 22,R5 is hydrogen or a functional group;

    Z and Z'"'"' are, independently of each other, hydroxyl, mercapto, SeH, C1 -C22 -alkoxy, --O--(CH2)b --NR6 R7, in which b is an integer from 1 to 6, and R7 is C1 -C6 -alkyl, or R6 and R7, 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 also heteroaryl, and aryl is optionally substituted by 1, 2, or 3 identical or different radicals from the group carboxyl, amino, nitro, C1 -C4 -alkylamino, C1 -C6 -alkoxy, hydroxyl, halogen and cyano, C1 -C18 -alkylmercapto, NHR3, NR3 R4, a radical of the formula III or a group which favors intracellular uptake or which serves as the label of A DNA probe, or, when the olionucleotide analog hybridizes to the target nucleic acid, attacks the latter with binding, crosslinking or cleavage,and the curved bracket indicates that R2 and the adjacent radical Y or Y'"'"' can be located either in the 2'"'"' and 3'"'"' positions or else, conversely, in the 3'"'"' and 2'"'"' positions, 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, whereB are, independently of each other, a base which is customary in nucleotide chemistry, where at least one B is a base of the formula IV ##STR20## in which E and F are, independently of each other, H, OH, or NH2.

      

    

  

  
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