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US 5,874,553 AGranted
Phosphonomonoester nucleic acids, process for their preparation, and their use
AssigneeHoechst Aktiengesellschaft
InventorsAnuschirwan Peyman, Eugen Uhlmann, Gerhard Breipohl, Holger Wallmeier
Life of this patent
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Abstract
Novel oligonucleotide analogs of the formula (I) are described, ##STR1## in which A, B, D, G, L, P, Q, Q', R.sup.5, R.sup.6, X, Y, Z and n are as defined in the description, which have useful physical, biological and pharmacological properties, as well as a process for their preparation. Their application relates to use as inhibitors of gene expression (antisense oligonucleotides, ribozymes, sense oligonucleotides and triplex-forming oligonucleotides), as probes for the detection of nucleic acids and as auxiliaries in molecular biology.
Claims30
A compound of formula I ##STR37## in which n is a number from zero to 100;
- A independently of one another is a single bond, a methylene group or a group of formula IIa or IIb;
- ##STR38## in which M is a single bond, --O--, --S-- or --NR.sup.1 --, where R.sup.1 is hydrogen or (C.sub.1 -C.sub.6)-alkyl optionally substituted by hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio or amino;
- R.sup.2 and R.sup.3 independently of one another are hydrogen, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio, amino, halogen, or (C.sub.1 -C.sub.6)-alkyl optionally substituted by hydroxyl, (C.sub.1 -C.sub.6)-alkoxy or (C.sub.1 -C.sub.6)-alkylthio;
- p and q independently of one another are zero to 5;
- and
- r and s independently of one another are zero to 5;
- B independently of one another is hydrogen, hydroxyl, (C.sub.1 -C.sub.20)-alkyl, (C.sub.1 -C.sub.20)-alkoxy, (C.sub.1 -C.sub.20)-alkylthio, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkoxy, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkythio, an aromatic group or a heterocyclic group, wherein the alkyl, alkyl portion of alkoxy or alkylthio, aromatic or heterocyclic group is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, --NR.sup.9 R.sup.10, oxo, --C(O)OR.sup.8, --C(O)NR.sup.9 R.sup.10, --CN, --F, --Cl, --Br, --NO.sub.2, (C.sub.2 -C.sub.6)-alkoxyalkyl, --S(O).sub.m R.sup.8 , --(C.sub.1 -C.sub.6)--alkyl--S(O).sub.m R.sup.8, --NHC(.dbd.NH)NHR.sup.8, --C(.dbd.NH)NHR.sup.9, NR.sup.9 C(.dbd.O)R.sup.8, .dbd.NOR.sup.8, NR.sup.9 C(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.9 R.sup.10, --NR.sup.9 C(.dbd.O)NR.sup.9 R.sup.10, a natural nucleobase, an unnatural nucleobase or a reporter ligand, with the proviso that at least one B moiety is a nucleobase;
- m is zero, 1 or 2;
- or,
- A-B independent of other A and B groups, can be a D- or L-amino acid condensed on via the carboxyl group or a peptide containing amino acids having a length of up to 5 amino acid residues, with the proviso that at least one B moiety is a nucleobase;
- L independently of one another is N or R.sup.1 N.sup.30 , where R.sup.1 is as defined above;
- and
- Y' is .dbd.O, .dbd.S, .dbd.CH.sub.2, .dbd.C(CH.sub.3).sub.2 or .dbd.NR.sup.1, where R.sup.1 is as defined above;
- D and G each independently represent CR.sup.5 R.sup.6 which can be the same or different;
- R.sup.5 and R.sup.6 independently of one another are hydrogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.20)-aryl, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkyl, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio, wherein the alkyl, alkyl portion of alkoxy or alkylthio, or aryl group is optionally substituted by SR.sup.1 or NR.sup.1 R.sup.1, where R.sup.1 is as defined above and R.sup.1 independently of R.sup.1 has the same meaning as R.sup.1 ;
- X independently of one another is --O--, --S-- or --NR.sup.1 --, in which R.sup.1 is as defined above;
- Y independently of one another is .dbd.O or .dbd.S;
- Z independently of one another is --OR.sup.8, --NR.sup.9 R.sup.10 or X'Q", where X' is defined as X above and Q" is defined as Q below;
- R.sup.8 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.6 -C.sub.12)-aryl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.6)-alkyl, wherein alkyl is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, F, Cl or Br and wherein aryl is optionally substituted 1-3 times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkyl, F, Cl, Br, NO.sub.2, --NR.sup.9 R.sup.10, --C(O)OH, --C(O)O--(C.sub.1 -C.sub.6)-alkyl or -C(O)NR.sup.9 R.sup.10 ;
- R.sup.9 and R.sup.10 independently of one another are hydrogen, (Cl-C.sub.18)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.3 -C.sub.18)-alkynyl, (C.sub.6 -C.sub.12)-aryl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.6)-alkyl, where alkyl is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, F, Cl or Br;
- or R.sup.9 and R.sup.10 form a 4 to 7-membered ring together with the N atom in --NR.sup.9 R.sup.10 ;
- Q and Q' independently of one another are R.sup.8, modified or unmodified oligonucleotides or conjugates which a) favorably affect the properties of antisense oligonucleotides, b) affect the properties of triple helix-forming oligonucleotides, c) serve as a label of a DNA probe, or d) during the hybridization of the oligonucleotide analog to the target nucleic acid, attack the target nucleic acid with binding or cross-linking;
- or Q and Q' alone or together are a single bond in a cyclic molecule;
- or Q and Q', when neither is hydrogen, can be linked together to form a cyclic molecule.
21 more elements
A compound having one of the formulae:
- 5'-Q.sup.11 -OLIGO-(PMENA-OLIGO)a-Q.sup.12 ;
- 5'-Q.sup.13 -PMENA-OLIGO-PMENA-Q.sup.14 ;
- 5'-Q.sup.15 -PMENA-(OLIGO-PMENA)a-Q.sup.16 ;
- or
- 5'-OLIGO-(PMENA-OLIGO)a;
- wherein a is 1-20, OLIGO represents an unmodified or modified oligonucleotide, and PMENA represents a compound of formula I':
- ##STR69## in which A independently of one another is a single bond, a methylene group or a group of formula IIa or IIb;
- ##STR70## in which M is a single bond, --O--, --S-- or --NR.sup.1 --, where R.sup.1 is hydrogen or C.sub.1 -C.sub.6)-alkyl optionally substituted by hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio or amino;
- R.sup.2 and R.sup.3 independently of one another are hydrogen, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio, amino, halogen, or (C.sub.1 -C.sub.6)-alkyl optionally substituted by hydroxyl, (C.sub.1 -C.sub.6)-alkoxy or (C.sub.1 -C.sub.6)-alkylthio;
- p and q independently of one another are zero to 5;
- and
- r and s independently of one another are zero to 5;
- B independently of one another is hydrogen, hydroxyl, (C.sub.1 -C.sub.20)-alkyl, (C.sub.1 -C.sub.20)-alkoxy, (C.sub.1 -C.sub.20)-alkylthio, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkoxy, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkythio, an aromatic group or a heterocyclic group, wherein the alkyl, alkyl portion of alkoxy or alkylthio, aromatic or heterocyclic group is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, -NR.sup.9 R.sup.10, oxo, --C(O)OR.sup.8, --C(O)NR.sup.9 R.sup.10, --CN, --F, --Cl, --Br, --NO.sub.2, (C.sub.2 -C.sub.6)-alkoxyalkyl, --S(O).sub.m R.sup.8, --(C.sub.1 -C.sub.6)--alkyl--S(O).sub.m R.sup.8, --NHC(.dbd.NH)NHR.sup.8, --C(.dbd.NH)NHR.sup.8, NR.sup.9 C(.dbd.O)R.sup.8, .dbd.NOR.sup.8, NR.sup.9 C(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.9 R.sup.10, --NR.sup.9 C(.dbd.O)NR.sup.9 R.sup.10, a natural nucleobase, an unnatural nucleobase or a reporter ligand, with the proviso that at least one B moiety is a nucleobase;
- m is zero, 1 or 2;
- or,
- A-B independent of other A and B groups, can be a D- or L-amino acid condensed on via the carboxyl group or a peptide containing amino acids having a length of up to 5 amino acid residues, with the proviso that at least one B moiety is a nucleobase;
- L independently of one another is N or R.sup.1 N.sup.+, where R.sup.1 is as defined above;
- and
- Y' is .dbd.O, .dbd.S, .dbd.CH.sub.2'. .dbd.C(CH.sub.3).sub.2 or .dbd.NR.sup.1, where R.sup.1 is as defined above;
- D and G each independently represent CR.sup.5 R.sup.6 which can be the same or different;
- R.sup.1 and R.sup.6 independently of one another are hydrogen, (C.sup.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.20)-aryl, (C.sub.6 -C.sub.20)-aryl-(C.sub.1 -C.sub.6)-alkyl, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy, (C.sub.1 -C.sub.6)-alkylthio, wherein the alkyl, alkyl portion of alkoxy or alkylthio, or aryl group is optionally substituted by SR.sup.1 or NR.sup.1 R.sup.1', where R.sup.1 is as defined above and R.sup.1 independently of R.sup.1 has the same meaning as R.sup.1 ;
- X independently of one another is --O--, --S-- or --NR.sup.1 --, in which R.sup.1 is as defined above;
- Y independently of one another is .dbd.O or .dbd.S;
- Z independently of one another is --OR.sup.8, --NR.sup.9 R.sup.10 or X'Q", where X' is defined as X above and Q" is R.sup.8, modified or unmodified oligonucleotides or conjugates which a) favorably affect the properties of antisense oligonucleotides, b) affect the properties of triple helix-forming oligonucleotides, c) serve as a lable of a DNA probe, or d) during the hybridization of the oligonucleotide analog to the target nucleic acid, attack the target nucleic acid with binding or crosslinking;
- R.sup.8 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.6 -C.sub.12)-aryl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.6)-alkyl, wherein alkyl is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, F, Cl or Br and wherein aryl is optionally substituted 1-3 times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkyl, F, Cl, Br, NO.sub.2, --NR.sup.9 R.sup.10, --C(O)OH, --C(O)O--(C.sub.1 -C.sub.6)-alkyl or --C(O)NR.sup.9 R.sup.10 ;
- R.sup.9 and R.sup.10 independently of one another are hydrogen, (C.sub.1 -C.sub.18)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.3 -C.sub.18)-alkynyl, (C.sub.6 -C.sub.12)-aryl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.6)-alkyl, where alkyl is optionally substituted one or more times by hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, F, Cl or Br;
- or R.sup.9 and R.sup.10 form a 4 to 7-membered ring together with the N atom in --NR.sup.9 R.sup.10 ;
- and wherein Q.sup.13 and Q.sup.14 either both represent hydrogen or together form a bond in a cyclic molecule;
- Q.sup.15 and Q.sup.16 either both represent hydrogen or together form a bond in a cyclic molecule;
- and Q.sup.11 and Q.sup.12 form a single bond in a cyclic molecule.
27 more elements
Dependencies are inferred from the claim text.