Back to results
US 5,886,177 AGranted
Phosphate linked oligomers
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Oscar L. Acevedo, Peter W. Davis, David J. Ecker, Normand Hebert
Life of this patent
Estimating the term…
Abstract
Novel ethylene glycol compounds bearing various functional groups are used to prepare oligomeric structures. The ethylene glycol monomers can be joined via standard phosphate linkages including phosphorothioate, phosphodiester, and phosphoramidate linkages. Useful functional groups include nucleobases as well as polar groups, hydrophobic groups, ionic groups, aromatic groups and/or groups that participate in hydrogen-bonding.
Claims22
A compound having structure II:
- ##STR3## wherein:
- X is H, a phosphate group, an activated phosphate group, an activated phosphite group, a solid support, a conjugate group, or an oligonucleotide;
- Y is H, a hydroxyl protecting group, a conjugate group or an oligonucleotide;
- E is O or S;
- EE is O.sup.- or N(Y.sub.0)T.sub.0, provided that at least one EE is N(Y.sub.0)T.sub.0 ;
- Y.sub.0 is H, or Q.sub.2 !jj-Z.sub.2 ;
- T.sub.0 is Q.sub.1 !kk-Z.sub.1, or together Y.sub.0 and T.sub.0 are joined in a nitrogen heterocycle;
- Q.sub.1 and Q.sub.2 independently, are C.sub.2 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.4 -C.sub.7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C.sub.7 -C.sub.14 aralkyl;
- jj and kk independently, are 0 or 1;
- Z.sub.1 and Z.sub.2, independently, are H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, C.sub.6 -C.sub.14 aryl, C.sub.7 -C.sub.15 aralkyl, a halogen, CH.dbd.O, OR.sub.1, SR.sub.2, NR.sub.3 R.sub.4, C(.dbd.NH)NR.sub.3 R.sub.4, CH(NR.sub.3 R.sub.4), NHC(.dbd.NH)NR.sub.3 R.sub.4, CH(NH.sub.2)C(.dbd.O)OH, C(.dbd.O)NR.sub.3 R.sub.4, C(.dbd.O)OR.sub.5, a metal coordination group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group;
- Z is L.sub.1, L.sub.1 -G.sub.1, L.sub.2, L.sub.2 -G.sub.2, NR.sub.3 R.sub.4, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group, provided that at least two of Z and Z.sub.m are different moieties, and wherein Z and each Z.sub.m are in a random sequence;
- L.sub.1 is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms;
- L.sub.2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;
- G.sub.1 is halogen, OR.sub.1, SR.sub.2, NR.sub.3 R.sub.4, C(.dbd.NH)NR.sub.3 R.sub.4, NHC(.dbd.NH)NR.sub.3 R.sub.4, CH.dbd.O, C(.dbd.O)OR.sub.5, CH(NR.sub.3 R.sub.4) (C(.dbd.O)OR.sub.5) , C(.dbd.O)NR.sub.3 R.sub.4, a metal coordination group, or a phosphate group;
- G.sub.2 is halogen, OH, SH, SCH.sub.3, or NR.sub.3 R.sub.4 ;
- R.sub.1 is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group;
- R.sub.2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;
- R.sub.3 and R.sub.4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;
- R.sub.5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;
- Q is L.sub.1, G.sub.3, L.sub.1 -G.sub.3 or G.sub.3 -L.sub.1 -G.sub.3 ;
- G.sub.3 is NR.sub.3, C(.dbd.O), C(.dbd.S), C(O)--O, C(O)--NH, C(S)--O, C(S)--NH or S(O).sub.2, NR.sub.3 C(.dbd.O), NR.sub.3 C(.dbd.S), NR.sub.3 C(O)--O, NR.sub.3 C(O)--NH, NR.sub.3 C(S)--O, NR.sub.3 C(S)--NH or NR.sub.3 S(O).sub.2 ;
- n is 0 or 1;
- j is 1 to 6;
- and
- m is 1 to 50.
22 more elements
A compound having structure II:
- ##STR4## wherein:
- X is H, a phosphate group, an activated phosphate group, an activated phosphite group, a solid support, a conjugate group, or an oligonucleotide;
- Y is H, a hydroxyl protecting group, a conjugate group or an oligonucleotide;
- E is O or S;
- EE is O or N(Y.sub.0)T.sub.0, provided that at least one EE is N(Y.sub.0)T.sub.0 ;
- Y.sub.0 is H, or Q.sub.2 !jj-Z.sub.2 ;
- To is Q.sub.1 !.sub.kk -Z.sub.1, or together Y.sub.0 and T.sub.0 are joined in a nitrogen heterocycle;
- Q.sub.1 and Q.sub.2 independently, are C.sub.2 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.4 -C.sub.7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C.sub.7 -C.sub.14 aralkyl;
- jj and kk independently, are 0 or 1;
- Z.sub.1, and Z.sub.2, independently, are H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, C.sub.6 -C.sub.14 aryl, C.sub.7 -C.sub.14 aralkyl, a halogen, CH.dbd.O, OR.sub.1, SR.sub.2, NR.sub.3 R.sub.4, C(.dbd.NH)NR.sub.3 R.sub.4, CH(NR.sub.3 R.sub.4), NHC(.dbd.NH)NR.sub.3 R.sub.4, CH(NH.sub.2)C(.dbd.O)OH, C(.dbd.O)NR.sub.3 R.sub.4, C(.dbd.O)OR.sub.5, a metal coordination group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group;
- Z is L.sub.1, L.sub.1 -G.sub.1, L.sub.2, L.sub.2 -G.sub.2, NR.sub.3 R.sub.4, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group, provided that at least two of Z and Z.sub.m are different moieties;
- L.sub.1 is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms;
- L.sub.2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;
- G.sub.1 is halogen, OR.sub.1, SR.sub.2, NR.sub.3 R.sub.4) C(.dbd.NH)NR.sub.3 R.sub.4, NHC(.dbd.NH)NR.sub.3 R.sub.4, CH.dbd.O, C(.dbd.O)OR.sub.5, CH(NR.sub.3 R.sub.4) (C(.dbd.O)OR.sub.5), C(.dbd.O)NR.sub.3 R.sub.4, a metal coordination group, or a phosphate group;
- G.sub.2 is halogen, OH, SH, SCH.sub.3, or NR.sub.3 R.sub.4 ;
- R.sub.1 is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group;
- R.sub.2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;
- R.sub.3 and R.sub.4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;
- R.sub.5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;
- Q is L.sub.1, G.sub.3, L.sub.1 -G.sub.3 or G.sub.3 -L.sub.1 -G.sub.3 ;
- G.sub.3 is NR.sub.3, C(.dbd.O), C(.dbd.S), C(O)--O, C(O)--NH, C(S)--O, C(S)--NH or S(O).sub.2, NR.sub.3 C(.dbd.O), NR.sub.3 C(.dbd.S), NR.sub.3 C(O)--O, NR.sub.3 C(O)--NH, NR.sub.3 C(S)--O, NR.sub.3 C(S)--NH or NR.sub.3 S(O).sub.2 ;
- N is 0 or 1;
- j is 1 to 6;
- and
- m is 1 to 50.
22 more elements
Dependencies are inferred from the claim text.