US2003065146A1PendingUtilityA1
Monomeric diols, phosphate linked oligomers formed therefrom and processes for preparing
Priority: Jan 11, 1994Filed: Jun 3, 2002Published: Apr 3, 2003
Est. expiryJan 11, 2014(expired)· nominal 20-yr term from priority
A61P 43/00A61P 29/00C07F 9/65616C07F 9/59C07F 9/572C07F 9/6547C07F 9/6561C07F 9/65038C07F 9/2408C07F 9/2429C07B 2200/11C07F 9/6533A61P 17/00A61P 17/04C07F 9/65335C07H 21/00A61P 1/00C07F 9/143C07F 9/6512A61P 1/04B01J 2219/00592C07F 9/6521C07F 9/6506B01J 2219/00695C07F 9/65031C07F 9/5728
48
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Claims
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 phosphodiester and phosphorothioate 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.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound having structure I:
wherein:
X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support;
Y is H or a hydroxyl protecting group;
Z is L 1 , L 1 -G 1 , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group;
L 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 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;
G 1 is halogen, OR 1 , SR 2 , NR 3 R 4 , C(═NH)NR 3 R 4 , NHC(═NH)NR 3 R 4 , CH═O, C(═O)OR 5 , CH(NR 3 R 4 ) (C(═O)OR 5 ), C(═O)NR 3 R 4 , metal coordination group, or a phosphate group;
G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ;
R 1 is H, alkyl having 1 to about 5 carbon atoms, or a hydroxyl protecting group;
R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;
R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;
R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;
Q is L 1 , G 3 , L 1 -G 3 or G 3 -L 1 -G 3 ;
G 3 is NR 3 C(═O), C(═S), C(O)-O, C(Q)-NH, C(S)-O, C(S)-NH or S(O) 2 , NR 3 C(═O), NR 3 C(═S), NR 3 C(O)-O, NR 3 C(O)-NH, NR 3 C(S)-O, NR 3 C(S)-NH or NR 3 S(O) 2 ;
n is 0 or 1; and
j is 1 to 6;
provided that:
if n=0 and Z is NH 2 , adenine, guanine, cytosine, uracil or thymine and if one of X or Y is 5H then the other of X or Y is not H; and
if n=0 and Q is alkyl-NH, then Z is not biotin or phosphotyrosinyl.
2 . The compound of claim 1 wherein Y is a hydroxyl protecting group.
3 . The compound of claim 2 wherein Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl.
4 . The compound of claim 1 wherein X is H, an activated phosphite group, or a solid support.
5 . The compound of claim 4 wherein X is a phosphoramidite.
6 . The compound of claim 1 wherein n is 1 and Q is a carbonyl, thiocarbonyl, carboxy, acetyl, amido, succinyl, carbamoyl, thiocarbamoyl, ureido, thioureido or sulfonamido acyl group.
7 . The compound of claim 1 wherein Z is said nitrogen-containing heterocycle.
8 . The compound of claim 7 wherein said nitrogen-containing heterocycle is imidazole, pyrrole or carbazole.
9 . The compound of claim 8 wherein Z is imidazole or carbazole.
10 . The compound of claim 1 wherein Z is a purine or a pyrimidine.
11 . The compound of claim 10 wherein X is an activated phosphite group, Y is a hydroxyl protecting group, and Z is adenine, guanine, cytosine, uridine or thymine.
12 . The compound of claim 1 wherein Z is polyethylene glycol.
13 . The compound of claim 1 wherein Z is alkyl having 1 to about 20 carbon atoms.
14 . The compound of claim 1 wherein Z is C 1 -C 6 alkyl-NH 2 .
14 . The compound of claim 1 wherein Z is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms.
16 . The compound of claim 15 wherein Z is fluorenylmethyl, phenyl or benzyl.
17 . The compound of claim 1 wherein Z is glutamyl.
18 . A compound having structure II:
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;
Z is L 1 , L 1 -G 1 , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group;
L 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 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;
G 1 is halogen, OR 1 , SR 2 , NR 3 R 4 , C(═NH)NR 3 R 4 , NHC(═NH)NR 3 R 4 , CH═O, C(═O)OR 5 , CH(NR 3 R 4 ) (C(═O)OR 5 ), C(═O)NR 3 R 4 , a metal coordination group, or a phosphate group;
G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ;
R 1 is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group;
R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;
R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;
R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;
Q is L 1 , G 3 , L 1 -G 3 or G 3 -L 1 -G 3 ;
G 3 is NR 3 , C(═O), C(═S), C(O)-O, C(O)-NH, C(S)-O, C(S)-NH or S (O) 2 , NR 3 C(═O), NR 3 C (═S), NR 3 C(O)-O, NR 3 C(O)-NH, NR 3 C(S)-O, NR 3 C (S)-NH or NR 3 S(O) 2 ;
n is 0 or 1;
j is 1 to 6; and
m is 1 to 50.
19 . The compound of claim 18 wherein Y is a hydroxyl protecting group.
20 . The compound of claim 19 wherein Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl.
21 . The compound of claim 18 wherein X is H, an activated phosphite group, or a solid support.
22 . The compound of claim 21 wherein X is a phosphoramidite.
23 . The compound of claim 18 wherein n is 1 and Q is a carbonyl, thiocarbonyl, carboxy, acetyl, amido, succinyl, carbamoyl, thiocarbamoyl, ureido, thioureido, or sulfonamido acyl group.
24 . The compound of claim 18 wherein Z is a nitrogen-containing heterocycle.
25 . The compound of claim 24 wherein said nitrogen-containing heterocycle is imidazole, pyrrole or carbazole.
26 . The compound of claim 25 wherein Z is imidazole or carbazole.
27 . The compound of claim 18 wherein Z is a purine or a pyrimidine.
28 . The compound of claim 27 wherein Z is adenine, guanine, cytosine, uridine or thymine.
29 . The compound of claim 28 wherein n is 0.
30 . The compound of claim 18 wherein Z is alkyl having 1 to about 20 carbon atoms.
31 . The compound of claim 18 wherein Z is C 1 -C 6 alkyl-NH 2 .
32 . The compound of claim 18 wherein Z is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms.
33 . The compound of claim 32 wherein Z is carbazole, phenyl or benzyl.
34 . The compound of claim 18 wherein Z is glutamyl.
35 . The compound of claim 18 wherein m is 1 to about 25.
36 . The compound of claim 18 wherein E is O.
37 . The compound of claim 18 wherein E is S.
38 . The compound of claim 18 wherein said Z groups of each of said monomers are in a predetermined sequence.
39 . The compound of claim 18 wherein said Z groups of each of said monomers are of a random sequence.
40 . A process for preparing a randomized oligomeric compound comprising:
selecting a group of monomers having structure I: wherein: X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support; Y is H or a hydroxyl protecting group; Z is L 1 , L 1 -G 1 , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; L 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 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms; G 1 is halogen, OR 1 , SR 2 , NR 3 R 4 , C(═H)NR 3 R 4 , NHC(═NH)NR 3 R 4 , CH═O, C(═O)OR 5 , CH(NR 3 R 4 ) (C(═O)OR 5 ), C(═O)NR 3 R 4 , a metal coordination group, or a phosphate group; G 1 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ; R 1 is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group; R 1 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group; R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group; R 5 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group; Q is L 1 , G 3 , L 1 -G 3 or G 3 -L 1 -G 3 ; G is NR 3 , C(═O), C(═S), C(O)-O, C(O)-NH, C(S)-C, C(S)-NH or S(O) 2 , NR 3 C(═O), NR 3 C(═S), NR 3 C(O)-O, NR 3 C(O)-NH, NR 3 C(S)-O, NR 3 C(S)-NH or NR 3 S(O) 2 ; n is 0 or 1; j is 1 to 6; and covalently bonding at least two of the monomers of said group to form said compound.
41 . The process of claim 40 wherein the Z moiety of at least one monomer of said group is different from the Z moiety of another monomer of said group.
42 . The process of claim 40 wherein said randomized oligomeric compound includes from 2 to 50 of said monomers.
43 . An oligomeric compound prepared via the process of claim 40 wherein said compound includes from 2 to 25 of said monomers.
44 . A chimeric oligomeric compound having a central region comprising a phosphodiester or a phosphorothioate oligodeoxynucleotide interspaced between flanking regions having structure II:
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;
Z is L 1 , L 1 -G 1 , L 2 , L 2 -G 2 , NR 3 R 4 , a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group;
L 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 2 is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;
G 1 is halogen, OR 1 , SR 2 , NR 3 R 4 , C(═NH)NR 3 R 4 , NHC(═NH)NR 3 R 4 , CH═O, C(═O)OR 5 , CH(NR 3 R 4 ) (C(═O)OR 5 ), C(═O)NR 3 R 4 , a metal coordination group, or a phosphate group;
G 2 is halogen, OH, SH, SCH 3 , or NR 3 R 4 ;
R 1 is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group;
R 2 is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;
R 3 and R 4 are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;
R 3 is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;
Q is L 1 , G 3 , L 1 -G 3 or G 3 -L 1 -G 3 ;
G 1 is NR 3 , C(═O), C(═S), C(O)-O, C(O)-NH, C(S)-O, C(S)-NH or S(O) 2 , NR 3 C(═O), NR 3 C(═S), NR 3 C(O)-O, NR 3 C(O)-NH, NR 3 C(S)-C, NR 3 C(S)-NH or NR 3 S(O) 2 ;
n is 0 or 1;
j is 1 to 6; and
m is 1 to 50.Join the waitlist — get patent alerts
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