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US 6,639,062 B2Granted
Aminooxy-modified nucleosidic compounds and oligomeric compounds prepared therefrom
AssigneeIsis Pharmaceuticals, Inc.
InventorsMuthiah Manoharan, Phillip Dan Cook, Thazha P. Prakash, Andrew M. Kawasaki
Life of this patent
Estimating the term…
Abstract
Nucleosidic monomers and oligomeric compounds prepared therefrom are provided which have increased nuclease resistance, substituent groups (such as 2′-aminooxy groups) for increasing binding affinity to complementary strand, and regions of 2′-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H. Such oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics.
Claims83
A compound of the structure:
- wherein:
- T4 is Bx or Bx—L where Bx is a heterocyclic base moiety;
- one of T1, T2 and T3 is L, hydrogen, hydroxyl, a protected hydroxyl or a sugar substituent group;
- another one of T1, T2 and T3 is L, hydroxyl, a protected hydroxyl, a connection to a solid support or an activated phosphorus-containing substituent group;
- the remaining one of T1, T2 and T3 is L, hydrogen, hydroxyl or a sugar substituent group provided that at least one of T1, T2, or T3 is L or Bx—L;
- said group L having one of the formulas;
- wherein:
- each m and mm is, independently, from 1 to 10;
- y is from 1 to 10;
- E is N(R1)(R2) or N═C(R1)(R2);
- each R1 and R2 is, independently, H, a nitrogen protecting group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, wherein said substitution is OR3, SR3, NH3+, N(R3)(R4), guanidino or acyl where said acyl is —C(═O)N(R3)(R4), —C(═O)R3, or —C(═O)OR3;
- provided that when T4 is Bx-L, R1 and R2 are not both H;
- or R1 and R2, together, are a nitrogen protecting group or are joined in a ring structure that optionally includes an additional heteroatom selected from N and O;
- and
- each R3 and R4 is, independently, H, C1-C10 alkyl, a nitrogen protecting group, or R3 and R4, together, are a nitrogen protecting group;
- or R3 and R4 are joined in a ring structure that optionally includes an additional heteroatom selected from N and O.
13 more elements
An oligomeric compound comprising a plurality of nucleoside units of the structure:
- wherein:
- T4 of each nucleoside unit is, independently, Bx or Bx—L where Bx is a heterocyclic base moiety;
- one of T5, T6 and T7 of each nucleoside unit is, independently, L, hydroxyl, a protected hydroxyl, a sugar substituent group, an activated phosphorus-containing substituent group, a connection to a solid support, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide;
- another of T5, T6 and T7 of each nucleoside unit is, independently, a nucleoside, a nucleotide, an oligonucleoside or an oligonucleotide;
- the remaining one of T5, T6 and T7 of each nucleoside unit is, independently, is L, hydrogen, hydroxyl, a protected hydroxyl, or a sugar substituent group;
- provided that on at least one of said nucleoside units T4 is Bx—L or at least one of T5, T6 and T7 is L;
- said group L having one of the formulas;
- wherein:
- each m and mm is, independently, from 1 to 10;
- y is from 1 to 10;
- E is N(R1)(R2) or N═C(R1)(R2);
- each R1 and R2 is, independently, H, a nitrogen protecting group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, wherein said substitution is OR3, SR3, NH3+, N(R3)(R4), guanidino or acyl where said acyl is —(C═O)N(R3)(R4), —C(═O)R3, or —C(═O)OR3,
- or R1 and R2, together, are a nitrogen protecting group or are joined in a ring structure that optionally includes an additional heteroatom selected from N and O;
- and
- each R3 and R4 is, independently, H, C1-C10 alkyl, a nitrogen protecting group, or R3 and R4, together, are a nitrogen protecting group or wherein R3 and R4 are joined in a ring structure that optionally includes an additional heteroatom selected from N and O.
12 more elements
An oligomeric compound specifically hybridizable with DNA or RNA comprising a sequence of linked nucleoside units, wherein:
- said sequence is divided into a first region having linked nucleoside units and a second region being composed of linked nucleoside units having 2′-deoxy sugar moieties;
- said linked nucleoside units of at least one of said first or second regions are connected by phosphorothioate linkages;
- at least one of said linked nucleoside units of said first region bearing a group L that is covalently attached to the heterocyclic base or the 2′,3′ or 5′ position of the sugar moiety;
- said group L having one of the formulas:
- wherein:
- each m and mm is, independently, from 1 to 10;
- y is from 1 to 10;
- E is N(R1)(R2) or N═C(R1)(R2);
- each R1 and R2 is, independently, H, a nitrogen protecting group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, wherein said substitution is OR3, SR3, NH3+, N(R3)(R4), guanidino or acyl where said acyl is —C(═O)N(R3)(R4), —C(═O)R3, or —C(═O)OR3;
- or R1 and R2, together, are a nitrogen protecting group or are joined in a ring structure that optionally includes an additional heteroatom selected from N and O;
- and
- each R3 and R4 is, independently, H, C1-C10 alkyl, a nitrogen protecting group, or R3 and R4, together, are a nitrogen protecting group;
- and
- or R3 and R4 are joined in a ring structure that optionally includes an additional heteroatom selected from N and O.
11 more elements
Dependencies are inferred from the claim text.