Polyamide-oligonucleotide derivatives, their preparation and use

A polyamide-oligonucleotide derivative of the formulae Ia and Ib as claimed in claim 1,

• 29
• wherein
• x is 1 to 5, where
• when x>1 r=s=1 and, at the same time,
• q=t=zero and o=n=zero to 5;
• q, r, s, t are, independently of one another, zero or 1, where the total of
• two or more adjacent q, r, s and t≧2;
• R2 is hydrogen, hydroxyl, C1-C18-alkoxy, halogen, azido or amino;
• B is, independently of one another, a base customary in nucleotide chemistry, and the “curved bracket” indicates that R2 and the adjacent substituent Li1 or Li3 can be in the 2′ position and 3′ position, respectively, or conversely in the 3′ position and 2′, respectively;
• Nu is a radical of the formulae IIa or IIb
• 30
• in which
• R2 and B are as defined above;
• U is hydroxyl, mercapto, C1-C18-alkyl, C1-C18-alkoxy, C6-C20-aryl, C6-C14-aryl-C1-C8-alkyl, NHR3 or NR3R4, and
• R3 is C1-C18-alkyl or C1-C4-alkoxy-C1-C4-alkyl, and
• R4 is C1-C18-alkyl or
• R3 and R4 is, together with the nitrogen atom carrying them, a 5-6-membered heterocyclic ring which can additionally contain another heteroatom from the series consisting of O, S, N;
• V is oxy, thio or imino;
• W is oxo or thioxo;
• Y is oxy, thio, methylene or imino;
• m is zero to 20;
• is zero to 20;
• D is a radical of the formula III
• 31
• in which B is as defined above;
• D′ is a radical of the formula IV
• 32
• in which B is as defined above;
• n is zero to 20;
• p is zero to 20;
• Li1, Li2, Li3 and Li4 are each, independently of one another, a structure of the formula V
• [(V′)-(G)-(G′)]ε(V)
• where, independently of one another,
• ε is 1 to 5,
• V′ is oxygen, NH, a bond or a radical of the formula VI
• 33
• in which
• U, V, W and Y are as defined above;
• G can be C1-C12-alkanediyl, where alkanediyl is unsubstituted or substituted by halogen, amino, hydroxyl, C1-C18-alkyl, C1-C18-alkoxy, C1-C14-aryl, or C6-C14-aryl-C1-C18-alkyl;
• C6-C14-aryl-di-C1-C12-alkanediyl, or a group of the formula (CH2CH2O)δCH2CH2 in which δ can be 1 to 11;
• or a bond;
• and
• G′ is oxy, thio, imino, —C(O)—, —C(O)NH—, a bond or a radical of the formula VI in which U, V, W and Y are as defined above;
• and
• F and F′ are linked by at least one bond and
• F is R0-(A)k-V— and
• F′ in formula Ia is -(Q)1-R1 and in formula Ib is V1-(A)1-R1,
• where
• R0 is hydrogen, C1-C18-alkanoyl, C1-C18-alkoxy-carbonyl, C3-C8-cycloalkanoyl, C7-C15-aroyl, C3-C13-heteroaroyl or a group which favors intracellular uptake of the oligomer or serves as labeling of a DNA probe or, in the hybridization of the oligomer onto the target nucleic acid, attacks the latter with binding, crosslinking or cleavage;
• or
• if k is zero, R0 is hydrogen or together with V is a radical of the formula VII
• 34
• in which
• Z and Z′ are, independently of one another, hydroxyl, mercapto, C1-C22-alkoxy, C1-C18-alkyl, C6-C20-aryl, C6-C14-aryl-C1-C18-alkyl, C1-C22-alkylthio, NHR3, NR3R4, or a group which favors intracellular uptake of the oligomer or serves as labeling of a DNA probe or, in the hybridization of the oligomer onto the target nucleic acid, attacks the latter with binding, cross-linking or cleavage, and in which
• R3, R4, V and W are as defined above;
• R1 is hydrogen or Qo
• where R1 is always only hydrogen when at the same time 1 is zero and in formula Ia t is zero and s is 1 and Li1 is a structure of the formula V with V′=bond, G=bond, ε=1 and G′=oxy, thio, imino or a radical of the formula VI with U=Z or
• in formula Ib q is 1 or q=r=zero and in F′=V1-(A)1-R1 with V1=V,
• A and Q are, independently of one another, the residue of a naturally occuring or not naturally occuring amino acid;
• Qo is hydroxyl, OR′, NH2, NHR″ with R′=C1-C18-alkyl and R=C1-C18-alkyl, C1-C18-aminoalkyl, C1-C18-hydroxyalkyl;
• V is as defined above;
• V1 is a bond or V, where in F′ only in formula Ib with q=zero and r=1 V1 is always a bond;
• k is zero to 10;
• is zero to 10;
• with the proviso that
• a) if in the compound of the formula Ia t is zero and s is 1, and Li1 is (V′)-(G)-(G′) with V′=a compound of the formula VI, G=C2-C12-alkylene and G′=CO, in F′=-(Q)1-R1 1 is zero to 10 and R1 is Q°;
• b) if in the compound of the formula Ia s=t=zero, Li2 is a bond;
• c) if in the compound of the formula Ib t is zero and s is 1, Li3 is a bond;
• d) if in the compound of the formula Ib s=t=zero, Li4 is a bond;
• where each nucleotide can be in its D or L configuration, and the base can be in the a or P position.