Pyrimidine derivatives for labeled binding partners
First Claim
1. A compound having the structure:
-
whereinR1 is a binding partner, a linker or H;
a and b independently are 0 or 1, provided that the total of a and b is 0 or 1;
A is independently N or C;
X is independently S, O, —
C(O)—
, NH or NCH2R6;
Y is —
C(O)—
;
Z is taken together with A to form a 5- or 6-membered aryl or heteroaryl ring structure wherein the heteroaryl ring has a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon, a single S and a single N ring heteroatom separated by a carbon, 2N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted or at least 1 nonbridging ring carbon atom is substituted with R6 or ═
O;
R6 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NO2, N(R3)2, C≡
N or halo, or an R6 is taken together with an adjacent R6 to complete a ring containing 5 or 6 ring atoms;
R3 is a protecting group or H;
and provided that where a is 0, b is 1 and R1 is
in which D2 is independently hydroxyl, protected hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and
D3 is H or OH;
then Z taken together with the A and carbon to which it is bound does not form an unsubstituted phenylene;
and tautomers, solvates and salts thereof.
0 Assignments
0 Petitions
Accused Products
Abstract
Compounds having particular interest as labels and various novel uses in diagnostics and therapeutics are provided which have structure (1)
wherein
R1 is a binding partner, a linker or H;
a and b are 0 or 1, provided that the total of a and b is 0 or 1;
A is N or C;
X is S, O, —C(O)—, NH or NCH2R6;
Y is —C(O)—;
Z is taken together with A to form an aryl or heteroaryl ring structure comprising 5 or 6 ring atoms wherein the heteroaryl ring comprises a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon atom, a single S and a single N ring heteroatom separated by a carbon atom, 2 N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted with other than H or at least 1 nonbridging ring carbon atom is substituted with R6 or ═O;
R6 is independently H, C1-C6 alkyl, C2-C6 alkeny, C2-C6 alkynyl, NO2, N(R3)2, C≡N or halo, or an R6 is taken together with an adjacent R6 to complete a ring containing 5 or 6 ring atoms;,
R3 is a protecting group or H; and tautomers, solvates and salts thereof;
and provided that where a is 0, b is 1, and R1 is
in which
D2 is independently hydroxyl, blocked hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and
D3 is H or OH;
then Z is not unsubstituted phenyl.
Also provided are novel intermediates and methods for the preparation and use of the structure (1) compounds.
-
Citations
47 Claims
-
1. A compound having the structure:
-
wherein R1 is a binding partner, a linker or H;
a and b independently are 0 or 1, provided that the total of a and b is 0 or 1;
A is independently N or C;
X is independently S, O, —
C(O)—
, NH or NCH2R6;
Y is —
C(O)—
;
Z is taken together with A to form a 5- or 6-membered aryl or heteroaryl ring structure wherein the heteroaryl ring has a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon, a single S and a single N ring heteroatom separated by a carbon, 2N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted or at least 1 nonbridging ring carbon atom is substituted with R6 or ═
O;
R6 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NO2, N(R3)2, C≡
N or halo, or an R6 is taken together with an adjacent R6 to complete a ring containing 5 or 6 ring atoms;
R3 is a protecting group or H;
and provided that where a is 0, b is 1 and R1 is
in whichD2 is independently hydroxyl, protected hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and
D3 is H or OH;
then Z taken together with the A and carbon to which it is bound does not form an unsubstituted phenylene;
and tautomers, solvates and salts thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
E—
CHR7—
R11—
(CH2)m1—
C(R8)((CH2)m1(R9))—
(CH2)m1—
(CH2)m1—
,E—
Q—
C6H4—
CH2—
;
E—
CHR7—
O—
CHR7—
O—
CHR7—
,E—
CHR7—
(CHR13)m1—
CHR14—
R10—
,H(CH2)m1CH(COOR20)(CH2)m1— D is an oligonucleotide coupling group;
D1 is independently F, H, O-alkyl, S-alkyl or an oligonucleotide coupling group, but only one D1 is a coupling group;
Q is independently —
C(R12)2—
CH2—
, C(R12)2—
O—
, —
CR12═
CR12—
, or —
C≡
C—
;
R7 is independently H or C1-C4 alkyl;
R8 is H or C1-C4 alkyl, C2-C4 alkenyl or azidomethyl;
R9 is halo, H or OR20 R10 is O, CH2 or a covalent bond;
R11 is O, S, CH2, CHF or CF2;
R12 is independently H or halogen;
R13 is H, halogen, OR20, CH3, CH2OR20 or C3-C6 acyloxyalkyl;
R14 is H, halogen, OR20, CH3, CH2OR20, C3-C6 acyloxymethyl, or C2-C6 acyloxy, R15 is CH2, CHF or O;
R16 is CH or S, provided that when R19 is O or S, or R15 is CH2, then R16 is not S;
R17 is H, OR20, halogen, N3, C1-C4 alkyl or C1-C4 alkoxy or is absent when R16 is S;
R18 is H, OR20, halogen, N3, C1-C4 alkyl or C1-C4 alkoxy;
R19 is O, S, CH2, CHF or CF2;
R20 is H or a protecting group;
m1 is independently 0 or an integer from 1 to 4; and
E is OH, OR20, O—
P(═
O)(O−
)2, and —
P(═
O)(O−
)2.
-
-
4. The compound of claim 1 wherein
R1 is H; - HOCH(CHR13)CH2—
;
ECH2OCH(CHR13)CH2—
;
orE is OH, OR20, O—
P(═
O)(O−
)2, and —
P(═
O)(O−
)2;
D2 is independently F, H, O-alkyl, S-alkyl or an oligonucleotide coupling group;
R13 is H, halogen, OR20, CH3, CH2OR20 or C3-C6 acyloxyalkyl; and
R20 is H or a protecting group.
- HOCH(CHR13)CH2—
-
5. The compound of claim 1 wherein Z is
A1 is N or CR6; - and
G is CH, S, O or NR4; and
R4 is H or C1-C6 alkyl.
- and
-
6. The compound of claim 5 wherein Z is
R4 is H or C1-C6 alkyl; - and
R5 is H, NO2 or C1-C6 alkyl.
- and
-
7. The compound of claim 5 wherein Z is
R2 is C1-C6 alkyl and R6 is H. -
8. The compound of claim 5 wherein Z is
-
9. The compound of claim 5 wherein adjacent R6 are taken together to complete a phenyl, thiazole, imidazole, oxazole, pyridine or pyrimidine ring.
-
10. The compound of claim 5 wherein G is S, O or NR4.
-
11. The compound of claim 5 wherein Z is
-
12. The compound of claim 5 wherein Z is
-
13. The compound of claim 1 wherein b is 0.
-
14. The compound of claim 1 wherein a is 1 and X is O.
-
15. The compound of claim 1 wherein b is 1 and a is 0.
-
16. The compound of claim 1 wherein A is C.
-
17. The compound of claim 1 wherein A is N.
-
18. The compound of claim 5 wherein A is N.
-
19. The compound of claim 5 wherein A is CH.
-
20. The compound of claim 1 wherein Z together with A and the carbon to which Z is bound completes a aryl ring containing 6 ring atoms.
-
21. The compound of claim 20 wherein the aryl ring contains a nonbridging ring carbon atom which is singly substituted with R6.
-
22. The compound of claim 1 wherein Z together with the A and carbon to which Z is bound completes a heteroaryl residue which has 1 ring N atom;
- 2 ring N atoms;
1 ring oxygen atom, 1 ring nitrogen and 1 ring sulfur atom separated by at least 1 carbon atom;
or 3 ring N atoms at least two of which are separated by at least 1 carbon atom.
- 2 ring N atoms;
-
23. The compound of claim 1 wherein Z together with the A and carbon to which Z is bound completes a heteroaryl ring consisting of 5 atoms, one of which is N.
-
24. The compound of claim 1 wherein A is C, b is 0, a is 1, and X is O, C(O) or S.
-
25. The compound of claim 1 wherein a and b are both 0.
-
26. The compound of claim 1 wherein A is N, b is 0, a is 1 and X is O.
-
27. The compound of claim 24 wherein Z together with A and the carbon to which Z is bound completes an aryl ring consisting of an unsubstituted aryl ring or an aryl ring substituted with R6.
-
28. The compound of claim 25 wherein A is C and Z together with A and the carbon to which Z is bound completes an unsubstituted pyridine ring or is a pyridine ring substituted with R6.
-
29. The compound of claim 1 wherein a is 0, b is 1 and Y is C(O).
-
30. An oligomer having the structure
wherein D is OH or blocked OH; -
D1 is an oligonucleotide coupling group or OH;
X1 is independently a phosphodiester linkage or a phosphodiester substitute linkage bonded to the 2′
or 3′
position of a furanose ring, and the remaining 2′
or 3′
position is substituted with R21;
R21 is H, OH, F, —
O-alkyl (C1-C12), —
S-alkyl (C1-C12), OC3H5, or SC3H5;
n is an integer from 0 to 98; and
B is a purine or pyrimidine base provided that at least one B has the structure
whereina and b are 0 or 1 provided that the total of a and b is 0 or 1;
A is N or C;
X is S, O, —
C(O)—
, NH or NCH2R6;
Y is —
C(O)—
;
Z together with a and the carbon which Z is bound to form 5- or 6-membered aryl or heteroaryl ring structure wherein the heteroaryl ring has a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon, a single S and a single N ring heteroatom separated by a carbon, 2N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted or at least 1 nonbridging ring carbon atom is substituted with R6 or ═
O;
R6 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NO2, N(R3)2, C≡
N or halo, or an R6 is taken together with an adjacent R6 to complete a ring containing 5 or 6 ring atoms;
R3 is a protecting group or H; and
provided that where a is 0, b is 1 and R1 is
in whichD2 is independently hydroxyl, protected hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G, T and C; and
D3 is H or OH;
then Z is not unsubstituted phenylene;
and tautomers, solvates and salts thereof. - View Dependent Claims (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)
A1 is N or CR6; G is CH, S, O or NR4; and
R4is H or C1-C6 alkyl;
and the tautomers, solvates and salts thereof.
-
-
33. The oligomer of claim 30 wherein Z together with A and the carbon to which Z is bound is
R4 is H or C1-C6 alkyl; - and
R5 is H, NO2 or C1-C6alkyl.
- and
-
34. The oligomer of claim 30 wherein Z together with A and the carbon to which Z is bound is
R2 is C1-C6 alkyl and R6 is H. -
35. The oligomer of claim 30 wherein Z together with A and the carbon to which Z is bound is
-
36. The oligomer of claim 30 wherein adjacent R6 are taken together to form phenyl, thiazole, imidazole, oxazole, pyridine or pyrimidine radicals.
-
37. The oligomer of claim 30 wherein Z together with A and the carbon to which Z is bound is
-
38. The oligomer of claim 30 wherein Z together with A and the carbon to which Z is bound is
-
39. The oligomer of claim 30 containing from 2 to about 30 nucleotide units.
-
40. The oligomer of claim 30 wherein R21 is H, OH, —
- O-allyl, —
O-methyl, —
O-ethyl or —
O-propyl.
- O-allyl, —
-
41. The oligomer of claim 30 wherein adjacent B groups have substructure (30).
-
42. The oligomer of claim 30 wherein bases other than substructure (30) consist of naturally-occurring nucleotide bases.
-
43. The oligomer of claim 30 wherein n is 0 to 20.
-
44. The oligomer of claim 30 wherein D1 is an H-phosphonyl group, a methylphosphonamidityl group, a β
- -cyanoethylphosphoramidityl group or an alkylphosphoramidityl group.
-
45. The oligomer of claim 30 wherein D is OH, —
- PO3, dimethoxytrityl-O or monomethoxytrityl-O.
-
46. The oligomer of claim 30 wherein a single B group having substructure (30) is located at the 5′
- or 3′
end of the oligomer.
- or 3′
-
47. The oligomer of claim 30 wherein at least one B is 5-(1-propynyl) cytosinyl or uracilyl.
Specification