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US 6,440,943 B1Granted
Oligonucleotides having site specific chiral phosphorothioate internucleoside linkages
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Muthiah Manoharan
Life of this patent
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Abstract
Novel chiral compounds that mimic and/or modulate the activity of wild-type nucleic acids are disclosed. In general, the compounds are phosphorothioate oligonucleotides wherein the 5′, and the 3′-terminal internucleoside linkages are chirally Sp and internal internucleoside linkages are chirally Rp.
Claims63
An oligomeric compound comprising a plurality of covalently-bound nucleosides;
- said compound having the formula:
- 5′-T1—(Nu—Sp)n—(Nu—Lp)m—(NU—Sp)p—Nu—T2-3′
- wherein:
- T1 and T2 are each, independently, hydroxyl, a protected hydroxyl, a covalent attachment to a solid support, a nucleoside, an oligonucleoside, a nucleotide, an oligonucleotide, a conjugate group or a 5′ or 3′ substituent group;
- each Sp is a chiral Sp phosphorothioate internucleoside linkage;
- each Lp is, independently, a chiral Rp phosphorothioate internucleoside linkage, a racemic phosphorothioate internucleoside linkage or an internucleoside linkage other than a chiral phosphorothioate internucleoside linkage;
- each n and m is, independently, from 1 to 100;
- each p is from 0 to 100;
- where the sum of n, m and p is from 3 to about 200;
- each Nu independently, has the formula:
- wherein:
- Bx is a heterocyclic base moiety;
- and
- R1 is H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group.
11 more elements
A nucleoside having the formula:
- wherein:
- Bx is a heterocyclic base moiety;
- R4 is a hydroxyl protecting group;
- R1 is H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group;
- and
- R2 is an Sp chiral auxiliary group.
3 more elements
A method of preparing an oligomeric compound of formula:
- 5′-T1—(Nu—Sp)n—(Nu—Lp)m—(NU—Sp)p—Nu—T2-3′
- wherein:
- each T1 and T2 is, independently, hydroxyl, a protected hydroxyl, a covalent attachment to a solid support, a nucleoside, an oligonucleoside, a nucleotide or an oligonucleotide, a conjugate group or a 5′ or 3′ substituent group;
- each Sp is an Sp phosphorothioate internucleoside linkage;
- each Lp is, independently, an Rp phosphorothioate internucleoside linkage, a racemic phosphorothioate internucleoside linkage or an internucleoside linkage other than a chiral Rp phosphorothioate internucleoside linkage;
- each n and m is, independently, from 1 to 100;
- each p is from 0 to 100 where the sum of n, m and p is from 3 to about 200;
- each Nu, independently, has the formula:
- wherein:
- Bx is a heterocyclic base moiety;
- and
- R1 is H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group;
- comprising the steps of:
- (a) providing a compound of formula:
- wherein:
- R4 is a labile hydroxyl protecting group;
- R3 is a covalent attachment to a solid support;
- (b) deblocking said labile hydroxyl protecting group to form a deblocked hydroxyl group;
- (c) optionally treating said deblocked hydroxyl group with a further compound having the formula:
- wherein:
- R2 is an Sp chiral auxiliary group;
- and a condensing reagent to form an extended compound;
- (d) optionally repeating steps (b) and (c);
- (e) treating said deblocked hydroxyl group with a compound having the formula:
- wherein:
- R5 is an Rp chiral auxiliary group or an activated phosphorus group;
- and a condensing reagent to form a further extended compound;
- (f) optionally repeating steps (e) and (f) to add further nucleosides;
- (g) deblocking said labile hydroxyl protecting group to form a deblocked hydroxyl group;
- (h) treating said deblocked hydroxyl group with a further compound having the formula:
- wherein:
- R1 is an Sp chiral auxiliary group;
- and a condensing reagent to form a protected oligomeric compound;
- and
- (i) optionally repeating steps (h) and (i) to add at additional nucleosides thereby forming a further protected oligomeric compound.
32 more elements
A compound of formula:
- wherein:
- R62 is H or a hydroxyl protecting group;
- R1 is H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group;
- B is a heterocyclic base moiety;
- and
- R61 is a chiral auxiliary selected from formulas I-VI:
3 more elements
A compound having the formula:
- wherein:
- B is a heterocyclic base moiety;
- q is 0 to about 50;
- R62 is H or a hydroxyl protecting group;
- R1 is H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group;
- R64 is H, a hydroxyl protecting group, or a linker to a solid support;
- R63 is a radical selected from the group consisting of
4 more elements
Dependencies are inferred from the claim text.