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US 5,602,240 AGranted
Backbone modified oligonucleotide analogs
AssigneesCiba-Geigy Corporation, Isis Pharmaceuticals, Inc.
InventorsAlain De Mesmaeker, Jacques Lebreton, Adrian Waldner, Phillip D. Cook
Life of this patent
Estimating the term…
Abstract
Oligonucleotide analogs are provided wherein phosphodiester inter-sugar linkages are replaced with four atom linking groups. Such linking groups include NR--C(O)--CH.sub.2 --CH.sub.2, NR--C(S)--CH.sub.2 --CH.sub.2, CH.sub.2 --NR--C(O)--CH.sub.2, CH.sub.2 --NR--C(S)--CH.sub.2, CH.sub.2 --CH.sub.2 --NR--C(O)--R--CH.sub.2, and CH.sub.2 --C(S)--NR--CH.sub.2. Methods for preparing and using these oligonucleotide analogs are also provided.
Claims20
An oligonucleotide analog comprising the structure:
- ##STR16## wherein:
- B.sub.x is a variable base moiety;
- Q is 0, CH.sub.2, CHF or CF.sub.2 ;
- X is H;
- OH;
- C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl;
- F;
- Cl;
- Br;
- CN;
- CF.sub.3 ;
- OCF.sub.3 ;
- OCN;
- O--, S--, or N-alkyl;
- O--, S--, or N-alkenyl;
- SOCH.sub.3 ;
- SO.sub.2 CH.sub.3 ;
- ONO.sub.2 ;
- NO.sub.2 ;
- N.sub.3 ;
- NH.sub.2 ;
- heterocycloalkyl;
- heterocycloalkaryl;
- aminoalkylamino;
- polyalkylamino;
- or substituted silyl;
- L.sub.1 --L.sub.2 --L.sub.3 --L.sub.4 is selected from NR--C(O)--CH.sub.2 --CH.sub.2 --, NR--C(S)--CH.sub.2 --CH.sub.2, CH.sub.2 --NR--C(O)--CH.sub.2, CH.sub.2 --NR--C(S)--CH.sub.2, CH.sub.2 --CH.sub.2 --NR--C(O), CH.sub.2 --CH.sub.2 --NR--C(S), C(O)--NR--CH.sub.2 --CH.sub.2, C(S)--NR--CH.sub.2 --CH.sub.2, CH.sub.2 --C(O)--NR--CH.sub.2, and CH.sub.2 --C(S)--NR--CH.sub.2 where R is hydrogen, alkyl, substituted alkyl, aralkyl, alkenyl, alkaryl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, or heterocycloaralkyl;
- and
- the remaining subunits are natural or synthetic.
26 more elements
A compound having the structure:
- ##STR17## wherein:
- B.sub.x is a variable base moiety;
- Q is 0, CH.sub.2, CHF or CF.sub.2 ;
- X is H;
- OH;
- C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl;
- F;
- Cl;
- Br;
- CN;
- CF.sub.3 ;
- OCF.sub.3 ;
- OCN;
- O--, S--, or N-alkyl;
- O--, S--, or N-alkenyl;
- SOCH.sub.3 ;
- SO.sub.2 CH.sub.3 ;
- ONO.sub.2 ;
- NO.sub.2 ;
- N.sub.3 ;
- NH.sub.2 ;
- heterocycloalkyl;
- heterocycloalkaryl;
- or aminoalkylamino;
- polyalkylamino;
- substituted silyl;
- L.sub.1 --L.sub.2 --L.sub.3 --L.sub.4 is selected from NR--C(O)--CH.sub.2 --CH.sub.2, NR--C(S)--CH.sub.2 --CH.sub.2, CH.sub.2 --NR--C(O)--CH.sub.2, CH.sub.2 --NR--C(S)--CH.sub.2, CH.sub.2 --CH.sub.2 --NR--C(O), CH.sub.2 --CH.sub.2 --NR--C(S), C(O)--NR--CH.sub.2 --CH.sub.2, C(S)--NR--CH.sub.2 --CH.sub.2, CH.sub.2 --C(O)--NR--CH.sub.2, and CH.sub.2 --C(S)--NR--CH.sub.2 where R is hydrogen, alkyl, substituted alkyl, aralkyl, alkenyl, alkaryl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, or heterocycloaralkyl;
- and
- R.sub.HP1 and R.sub.HP2 are, independently, H or a hydroxyl protecting group.
26 more elements
A process for preparing a compound having the structure:
- ##STR18## wherein:
- B.sub.x is a variable base moiety;
- Q is 0, CH.sub.2, CHF or CF.sub.2 ;
- X is H;
- OH;
- C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl;
- F;
- Cl;
- Br;
- CN;
- CF.sub.3 ;
- OCF.sub.3 ;
- OCN;
- O--, S--, or N-alkyl;
- O--, S--, or N-alkenyl;
- SOCH.sub.3 ;
- SO.sub.2 CH.sub.3 ;
- ONO.sub.2 ;
- NO.sub.2 ;
- N.sub.3 ;
- NH.sub.2 ;
- heterocycloalkyl;
- heterocycloalkaryl;
- aminoalkylamino;
- polyalkylamino;
- or substituted silyl;
- L.sub.1 --L.sub.2 --L.sub.3 --L.sub.4 is selected from NR--C(O)--CH.sub.2 --CH.sub.2, NR--C(S)--CH.sub.2 --CH.sub.2, CH.sub.2 --NR--C(O)--CH.sub.2, CH.sub.2 --NR--C(S)--CH.sub.2, CH.sub.2 --CH.sub.2 --NR--C(O), CH.sub.2 --CH.sub.2 --NR--C(S), C(O)--NR--CH.sub.2 --CH.sub.2, C(S)--NR--CH.sub.2 --CH.sub.2, CH.sub.2 --C(O)--NR--CH.sub.2, and CH.sub.2 --C(S)--NR--CH.sub.2 where R is hydrogen, alkyl, substituted alkyl, aralkyl, alkenyl, alkaryl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, or heterocycloaralkyl;
- and
- R.sub.HP1 and R.sub.HP2 are, independently, H or a hydroxyl protecting group.
- comprising the steps of:
- providing a first synthon having structure (I) and second synthon having structure (II):
- ##STR19## wherein:
- (a) R.sub.T is NH.sub.2 and R.sub.B is R.sub.A --CH.sub.2 --CH.sub.2 ;
- (b) R.sub.T is CH.sub.2 --NH.sub.2 and R.sub.B is R.sub.A --CH.sub.2 ;
- (c) R.sub.T is CH.sub.2 --CH.sub.2 --NH.sub.2 and R.sub.B is R.sub.A ;
- (d) R.sub.T is R.sub.A and R.sub.B is NH.sub.2 --CH.sub.2 --CH.sub.2 ;
- or
- (e) R.sub.T is CH.sub.2 --R.sub.A and R.sub.B is NH.sub.2 --CH.sub.2 ;
- where R.sub.A is C(O) OH, C(S)OH, or an activated derivative thereof;
- and
- coupling said first synthon and said second synthon to form an amide or thioamide linkage through said R.sub.T and R.sub.B groups.
38 more elements
Dependencies are inferred from the claim text.