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US 6,414,127 B1Granted
Pyrimidine derivatives for labeled binding partners
AssigneeIsis Pharmaceuticals, Inc.
InventorsKuei-Ying Lin, Mark D. Matteucci
Life of this patent
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Abstract
Compounds having structure (1) wherein R1 is —H a protecting group, a linker or a binding partner; and R2 and R34 are as defined in the specification. The invention also provides intermediates and methods make the structure (1) compounds, as well as methods to use the compounds as labels in diagnostic assays and to enhance binding to complementary bases.
Claims41
A compound having the structure (1):
- and tautomers, solvates and salts thereof, wherein
- R1 is —H or a binding partner having the structure 2, 2(A), 2(B), or 2(C):
- wherein
- D is —OH, protected —OH, an oligonucleotide coupling group or a solid support;
- D1 is an oligonucleotide coupling group, —OH, protected —OH or a solid support, wherein D1 is bonded to one 2′ or 3′ position in the oligonucleotide of structure (2) and the adjacent 2′ or 3′ position in structure (2) is substituted with R21, provided that D and D1 are not both an oligonucleotide coupling group or they are not both a solid support;
- D2 is —CO2R5, —C(O)N(R5)2, —SO3R5, —SO2N(R5)2 or an activated derivative of —CO2H or —SO3H;
- D3 is a protecting group, —H or —(CH2)2-6—N(R5)2,
- R4 independently a phosphodiester linkage or a phosphodiester substitute linkage, wherein R4 is bonded to one 2′ or 3′ position in the structure (2) oligonucleotide and the adjacent 2′ or 3′ position in structure (2) substituted with R21;
- R5 is independently —H or a protecting group;
- R21 is independently —H, —OH, halogen or a moiety that enhances the oligonucleotide against nuclease cleavage;
- R37 is independently —O—, —CH2— or —CF2—;
- n is an integer from 0 to 98;
- and
- B independently is a purine or pyrimidine base or a protected derivative thereof, provided that at least one B is a base of structure (3)
- R2 is A(Z)X1, wherein A is a spacer and Z independently is a label bonding group optionally bonded to a detectable label, but R2 is not amine, protected amine, nitro or cyano;
- R27 is independently —CH═, —N═, —C(C1-C8 alkyl)═ or —C(halogen)═, but no adjacent R27 are both —N═, or two adjacent R27 are taken together to form a ring having the structure,
- where Ra is independently —CH═, —N═, —C(C1-C8 alkyl)═ or —C(halogen)═, but no adjacent Ra are both —N═;
- R34 is —O—, —S— or —N(CH3)—;
- R40 independently is hydrogen, C1-C12 alkyl, C1-C12 substituted alkyl, a protecting group or both R40 together with the nitrogen atom to which they are attached form:
- and X1 is 1, 2 or 3.
17 more elements
A compound having the structure (1):
- or tautomers, solvates or salts thereof, wherein:
- R1 is an oligonucleotide, a protecting group, a linker or —H;
- R2 is —R6—(CH2)tNR5C(NR5)N(R3)2;
- R3 is independently —H, —CH3, —CH2CH3, —(CH2)w—N(R33)2 or a protecting group, or both R3 together are a protecting group;
- R5 independently H or a protecting group;
- R6 is independently —S—, —NR5—, —O—, —CH2—;
- R33 is independently —H, —CH3, —CH2CH3 or a protecting group;
- each R27 is, independently —CH═, —N═, —C(C1-C8 alkyl)═ or —C(halogen)═, with the proviso that no two adjacent groups R27 are both —N═;
- alternatively, adjacent R27 are taken together to form a ring having the structure:
- wherein each Ra is, independently —CH═, —N═, —C(C1-8 alkyl)═ or —C(halogen)═, with the proviso that no two adjacent groups Ra are both —N═;
- R34 is —O—, —S— or —N(CH3)—;
- w is independently 1 or 2;
- and
- t is 1, 2, 3, or 4.
11 more elements
A compound having the structure (4)
- or tautomers, solvates or salts thereof wherein,
- R1 is an oligonucleotide, a protecting group, a linker or —H;
- R2 is —R6—(CH2)tNR5C(NR5)N(R3)2;
- R3 is independently —H, —CH3, —CH2CH3, —(CH2)w—N(R33)2 or a protecting group, or both R3 together are a protecting group;
- R5 independently H or a protecting group;
- R6 is independently —S—, —NR5—, —O—, —CH2—;
- R33 is independently —H, —CH3, —CH2CH3 or a protecting group;
- each R27 is, independently —CH═, —N═, —C(C1-C8 alkyl)═ or —C(halogen)═, with the proviso that no two adjacent groups R27 are both —N═;
- or alternatively adjacent R27 are taken together to form a ring having the structure:
- wherein each Ra is, independently —CH═, —N═, —C(C1-8 alkyl)═ or —C(halogen)═, with the proviso that no two adjacent groups Ra are both —N═;
- t is 1, 2, 3, or 4;
- w is independently 1 or 2;
- R24 is a halogen;
- and
- R25 is —SH, —OH, ═S or ═O.
12 more elements
Dependencies are inferred from the claim text.