Polyamide-oligonucleotide derivatives, their preparation and use

1. A polyamide-oligonucleotide derivative of the formula Ia or a physiologically tolerated salt thereof

wherein

q=r=s=1 and t=zero;

R 2 is hydroxyl, C 1 -C 18 -alkoxy, halogen, azido or amino;

B is, independently of one another, a base customary in nucleotide chemistry or a prodrug form thereof, and

the “curved bracket” indicates that R 2 and the substituent Li 1 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

wherein

R 2 and B are defined above;

U is hydroxyl, mercapto, C 1 -C 18 -alkyl, C 1 -C 18 -alkoxy, C 6 -C 20 -aryl, C 6 -C 14 -aryl-C 1 -C 8 -alkyl, NHR 3 or NR 3 R 4 , and

R 3 is C 1 -C 18 -alkyl or C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, and

R 4 is C 1 -C 18 -alkyl, or

R 3 and R 4 form, together with the nitrogen atom carrying them, a 5 to 6-membered heterocyclic nng which can additionally contain another heteroatom chosen from 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;

o is zero to 20;

D is a radical of the formula III

wherein B is as defined above;

n is zero to 20;

p is zero to 20;

Li 1 and Li 2 , 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

wherein

U, V, W and Y are as defined above;

G is C 1 -C 12 -alkanediyl, where alkanediyl is unsubstituted or substituted by halogen, amino, hydroxyl, C 1 -C 18 -alkyl, C 1 -C 18 -alkoxy, C 6 -C 14 -aryl, or C 6 -C 14 -aryl-C 1 -C 18 -alkyl, C 6 -C 14 -aryl-di -C 1 -C 12 -alkanediyl, or a group of the formula (CH 2 CH 2 O) δ CH 2 CH 2 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 a bond to form cyclic compounds, or

F and F′ are end groups that cleave or crosslink nucleic acids; or

F is R 0 -(A) k -V- and

F′ is -(Q) 1 -R 1 ,

wherein

R 0 is hydrogen, C 1 -C 18 -alkanoyl, C 1 -C 18 -alkoxycarbonyl, C 3 -C 8 -cycloalkanoyl, C 7 -C 15 -aroyl, C 3 -C 13 -heteroaroyl or a group which, in the hybridization of the oligomer onto the target nucleic acid, crosslinks with, or cleaves the target nucleic acid: or if k is zero, R 0 is hydrogen or together with V is a radical of the formula VII

wherein

Z and Z′ are, independently of one another, hydroxyl, mercapto, C 1 -C 22 -alkoxy, C 1 -C 18 -alkyl, C 6 -C 20 -aryl, C 6 -C 14 -aryl-C 1 -C 18 -alkyl, C 1 -C 22 -alkylthio, NHR 3 , NR 3 R 4 , or a group which, in the hybridization of the oligomer onto the target nucleic acid, crosslinks with, or cleaves the target nucleic acid, and wherein

R 3 , R 4 , V and W are as defined above;

R 1 is hydrogen or Q o

where R 1 is always only hydrogen when at the same time I is zero and in formula Ia t is zero and s is 1 and Li 1 is a structure of the formula V with V′=bond, G=bond, δ=1 and G′=oxy, thio, imino or a radical of the formula VI with U=Z

A and Q are, independently of one another, the residue of a natural or unnatural amino acid;

Q o is hydroxyl, OR′, NH 2 , NHR″ with R′=C 1 -C 18 -alkyl and R″=C 1 -C 18 -alkyl, C 1 -C 18 -aminoalkyl, C 1 -C 18 -hydroxyalkyl;

V is as defined above;

V′ is a bond or V;

k is zero to 10;

I 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 Li 1 is (V′)-(G)-(G′) with V′=a compound of the formula VI, G=C 2 -C 12 -alkylene and G′=CO, then I is zero to 10 and R 1 is Q o in FI=-(Q)′ -R 1 ;

b) if in the compound of the formula Ia s=t=zero, Li 2 is a bond;

where each nucleotide can be in its D configuration, and the base can be in the α or β position.

2. The polyamide-oligonucleotide derivative of the formula Ia as claimed in claim 1 , wherein the base is in the β position.

3. A pharmaceutical containing an effective amount of a polyamide-oligonucleotide derivative as claimed in claim 1 .

4. The pharmaceutical as claimed in claim 3 , further comprising a pharmaceutically acceptable carrier.

5. A gene probe consisting of a polyamide-oligonucleotide derivative as claimed in claim 1 .

6. The polyamide-oligonucleotide derivative as claimed in claim 1 , wherein a nucleoside unit having a 3′-hydroxyl group is located on at least one end for use as a primer.

7. The polyamide-oligonucleotide derivative as claimed in claim 1 , wherein B, independently of one another, is chosen from adenine, cytosine, thymine, guanine, uracil, inosine, purine, 2,6-di-aminopunne, 7-deazaadenine, 7-deazaguanine, N 4 ,N 4 -ethanocytosine, N6,N 6 -ethano-2,6-diaminopurine, pseudoisocytosine, 5-methylcytosine, 5 fluorouracil, 5-(C 3 -C 6 )-alkynyluracil, 5-(C 3 -C 6 )-alkynylcytosine and prodrug forms thereof.

8. A polyamide-oligonucleotide derivative as claimed in claim 1 , wherein A and Q, independently of one another, are chosen from glycine, leucine, histidine, phenylalanine, cysteine, lysine, arginine, aspartic acid, glutamic acid, proline, tetrahydroisoquinoline-3-carboxylic acid, octahydroindole-2-carboxylic acid, and N-(2-aminoethyl)glycine.