US 5,696,248 AGranted

3'-modified oligonucleotide derivatives

AssigneeHoechst Aktiengesellschaft

InventorsAnuschirwan Peyman, Eugen Uhlmann, Carolin Carolus

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Abstract

Novel oligonucleotide analogs of the formulae I and II ##STR1## in which A, B, D, R.sup.1, R.sup.2, T, U, V, W, X, Y, Z, a, b, m, m', n and n' have the meanings stated in the description, with valuable physical, biological and pharmacological properties, and a process for the preparation thereof are described. Application thereof relates to the use as inhibitors of gene expression (antisense oligonucleotides, ribozymes, sense oligonucleotides and triplex forming oligonucleotides), as probes for detecting nucleic acids and as aids in molecular biology.

Claims21

Dependent claims

A compound of the formula I or formula II ##STR39## and the physiologically tolerated salts thereof, in which a is a number from zero to 20;

b is a number from zero to 20;
R.sup.1 is hydrogen, C.sub.1 -C.sub.18 -alkyl, C.sub.2 -C.sub.18 -alkenyl, C.sub.3 -C.sub.18 -alkynyl, C.sub.1 -C.sub.18 -alkylcarbonyl, C.sub.2 -C.sub.19 -alkenylcarbonyl, C.sub.3 -C.sub.19 -alkynylcarbonyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, or a radical of the formula III ##STR40## R.sup.2 is hydrogen, hydroxyl, C.sub.1 -C.sub.18 -alkoxy, halogen, azido or NH.sub.2 ;
D is hydroxyl, O--PO.sub.3.sup.2 ;
B is a base customary in nucleotide chemistry, for example natural bases or unnatural bases;
n is an integer from 1 to 100;
n' is an integer from zero to 50;
m is an integer from zero to 5;
m' in formula I is an integer from zero to 5;
m' in formula II is an integer from 1 to 5;
A is oxy, thioxy or methylene;
W is oxo, thioxo or selenoxo;
V is oxy or thio;
T is oxy, thio or imino;
Y is oxy, thio, imino or methylene;
X is hydroxyl or mercapto;
U is hydroxyl, mercapto, BH.sub.3, SeH, C.sub.1 -C.sub.18 -alkoxy, C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, NHR.sup.3, NR.sup.3 R.sup.4 or a radical of the formula IV
(OCH.sub.2 CH.sub.2).sub.p (CH.sub.2).sub.q CH.sub.2 R.sup.5 (IV)
in which
R.sup.3 is C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, --(CH.sub.2).sub.c --NH(CH.sub.2).sub.c !.sub.d --NR.sup.6 R.sup.6, in which c is an integer from 2 to 6 and d is an integer from zero to 6, and R.sup.6 is, independently of one another, hydrogen, C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl;
R.sup.4 is C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl or C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.8 -alkyl, or, in the case of NR.sup.3 R.sup.4, together with R.sup.3 and the nitrogen atom carrying them is a 5-6-membered heterocyclic ring which can additionally contain another hetero atom from the series consisting of O, S and N;
p is an integer from 1 to 100;
q is an integer from zero to 22;
R.sup.5 is hydrogen or a functional group such as hydroxyl, amino, NHR.sup.7, COOH, CONH.sub.2, COOR.sup.8 or halogen, in which R.sup.7 is C.sub.1 -C.sub.6 -alkyl and R.sup.8 is C.sub.1 -C.sub.4 -alkyl;
Z, Z' are, independently of one another, hydroxyl, mercapto, SeH, C.sub.1 -C.sub.22 -alkoxy, --O--(CH.sub.2).sub.b --NR.sup.7 R.sup.8, in which b is an integer from 1 to 6, and R.sup.7 is C.sub.1 -C.sub.6 -alkyl and R.sup.8 is C.sub.1 -C.sub.4 -alkyl, or R.sup.7 and R.sup.8 form, together with the nitrogen atom carrying them, a 3-6-membered rings C.sub.1 -C.sub.18 -alkyl, preferably C.sub.1 -C.sub.8 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, preferably C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.14 -aryl alkoxy, preferably C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy, where aryl also means heteroaryl and aryl is optionally substituted by 1, 2 or 3 identical or different radicals from the series consisting of carboxyl, amino, nitro, C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.6 -alkoxy, hydroxyl, halogen and cyano, or C.sub.1 -C.sub.18 -alkylmercapto, NHR.sup.3, NR.sup.3 R.sup.4, in which R.sup.3 and R.sup.4 are as defined above, or a group which favors intracellular uptake or acts as labelling of a DNA probe or, on hybridization of the oligonucleotide analog onto to the target nucleic acid, interacts with the latter by binding, crosslinking or cleavage, or a nucleoside or oligonucleotide linked via the 5' or 3' ends;
and
the curved parenthesis indicates that R.sup.2 and the adjacent phosphoryl radical can be located in the 2' and 3' positions or else conversely in the 3' and 2' positions, it being possible for each nucleotide to be in its D or L configuration and for the base B to be located in the .alpha. or .beta. position.

23 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula I or formula II ##STR39## and the physiologically tolerated salts thereof, in which a is a number from zero to 20;

b is a number from zero to 20;
R.sup.1 is hydrogen, C.sub.1 -C.sub.18 -alkyl, C.sub.2 -C.sub.18 -alkenyl, C.sub.3 -C.sub.18 -alkynyl, C.sub.1 -C.sub.18 -alkylcarbonyl, C.sub.2 -C.sub.19 -alkenylcarbonyl, C.sub.3 -C.sub.19 -alkynylcarbonyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, or a radical of the formula III ##STR40## R.sup.2 is hydrogen, hydroxyl, C.sub.1 -C.sub.18 -alkoxy, halogen, azido or NH.sub.2 ;
D is hydroxyl, O--PO.sub.3.sup.2 ;
B is a base customary in nucleotide chemistry, for example natural bases or unnatural bases;
n is an integer from 1 to 100;
n' is an integer from zero to 50;
m is an integer from zero to 5;
m' in formula I is an integer from zero to 5;
m' in formula II is an integer from 1 to 5;
A is oxy, thioxy or methylene;
W is oxo, thioxo or selenoxo;
V is oxy or thio;
T is oxy, thio or imino;
Y is oxy, thio, imino or methylene;
X is hydroxyl or mercapto;
U is hydroxyl, mercapto, BH.sub.3, SeH, C.sub.1 -C.sub.18 -alkoxy, C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, NHR.sup.3, NR.sup.3 R.sup.4 or a radical of the formula IV
(OCH.sub.2 CH.sub.2).sub.p (CH.sub.2).sub.q CH.sub.2 R.sup.5 (IV)
in which
R.sup.3 is C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, --(CH.sub.2).sub.c --NH(CH.sub.2).sub.c !.sub.d --NR.sup.6 R.sup.6, in which c is an integer from 2 to 6 and d is an integer from zero to 6, and R.sup.6 is, independently of one another, hydrogen, C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl;
R.sup.4 is C.sub.1 -C.sub.18 -alkyl, C.sub.6 -C.sub.20 -aryl or C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.8 -alkyl, or, in the case of NR.sup.3 R.sup.4, together with R.sup.3 and the nitrogen atom carrying them is a 5-6-membered heterocyclic ring which can additionally contain another hetero atom from the series consisting of O, S and N;
p is an integer from 1 to 100;
q is an integer from zero to 22;
R.sup.5 is hydrogen or a functional group such as hydroxyl, amino, NHR.sup.7, COOH, CONH.sub.2, COOR.sup.8 or halogen, in which R.sup.7 is C.sub.1 -C.sub.6 -alkyl and R.sup.8 is C.sub.1 -C.sub.4 -alkyl;
Z, Z' are, independently of one another, hydroxyl, mercapto, SeH, C.sub.1 -C.sub.22 -alkoxy, --O--(CH.sub.2).sub.b --NR.sup.7 R.sup.8, in which b is an integer from 1 to 6, and R.sup.7 is C.sub.1 -C.sub.6 -alkyl and R.sup.8 is C.sub.1 -C.sub.4 -alkyl, or R.sup.7 and R.sup.8 form, together with the nitrogen atom carrying them, a 3-6-membered rings C.sub.1 -C.sub.18 -alkyl, preferably C.sub.1 -C.sub.8 -alkyl, C.sub.6 -C.sub.20 -aryl, C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl, preferably C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.14 -aryl alkoxy, preferably C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy, where aryl also means heteroaryl and aryl is optionally substituted by 1, 2 or 3 identical or different radicals from the series consisting of carboxyl, amino, nitro, C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.6 -alkoxy, hydroxyl, halogen and cyano, or C.sub.1 -C.sub.18 -alkylmercapto, NHR.sup.3, NR.sup.3 R.sup.4, in which R.sup.3 and R.sup.4 are as defined above, or a group which favors intracellular uptake or acts as labelling of a DNA probe or, on hybridization of the oligonucleotide analog onto to the target nucleic acid, interacts with the latter by binding, crosslinking or cleavage, or a nucleoside or oligonucleotide linked via the 5' or 3' ends;
and
the curved parenthesis indicates that R.sup.2 and the adjacent phosphoryl radical can be located in the 2' and 3' positions or else conversely in the 3' and 2' positions, it being possible for each nucleotide to be in its D or L configuration and for the base B to be located in the .alpha. or .beta. position.

23 more elements