Single-stranded and double-stranded oligonucleotides comprising a 2-arylpropyl moiety
View Patent ↗The present invention provides single-stranded and double-stranded oligonucleotides comprising at least one aralkyl ligand that improvise the pharmacokinetic properties of the oligonucleotide. The aralkyl ligands of the present invention include naproxen, ibuprofen, and derivatives thereof. The present invention also provides method for modulating gene expression using the modified oligonucleotide compounds and compositions comprising those modified oligonucleotides.
1. A double-stranded oligonucleotide comprising a first strand and a second strand, wherein said first strand and said second are represented independently by formula I:
wherein
X is H, —P(O)(OM) 2 , —P(O)(OM)—O—P(O)(OM) 2 , —P(O)(Oalkyl) 2 , —P(O)(Oalkyl)-O—P(O)(Oalkyl) 2 , or -A 6 -[A 7 -(A 5 ) w ] y ;
X 1 is
or -A 8 -[A 9 -(A 5 ) w ] y ;
Z 1 represents independently for each occurrence O or S;
Z 2 represents independently for each occurrence —OH, —OM, -Oalkyl, -Oaryl, -Oaralkyl, —SH, —SM, -Salkyl, -Saryl, -Saralkyl, —N(R 3 )R 4 , —(C(R 11 ) 2 ) m N(R 11 ) 2 , —N(R 11 )(C(R 11 ) 2 ) m N(R 11 ) 2 , or alkyl;
R 1 and R 2 represent independently for each occurrence H, OH, F, -Oalkyl, -Oallyl, —O(C(R 11 ) 2 ) v OR 11 , —O(C(R 11 ) 2 ) v SR 11 , —O(C(R 11 ) 2 ) v N(R 11 ) 2 , —O(C(R 11 ) 2 ) v C(O)N(R 11 ) 2 , —N(R 11 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C(R 11 ) 2 ) v N((C 1 -C 6 )alkyl) 2 , —O(C(R 11 ) 2 ) v ON((C 1 -C 6 )alkyl) 2 , or —O-A 10 -[A 11 -(A 5 ) w ] y ;
R 3 and R 4 represent H or alkyl; or R 3 and R 4 taken together form a 3-, 4-, 5-, 6-, or 7-membered ring;
R 5 represents independently for each occurrence H, OH, F, -Oalkyl, -Oallyl, —O(C(R 11 ) 2 ) v OR 11 , —O(C(R 11 ) 2 ) v SR 11 , —O(C(R 11 ) 2 ) v N(R 11 ) 2 , —O(C(R 11 ) 2 ) v C(O)N(R 11 ) 2 , —N(R 11 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C(R 11 ) 2 ) v N((C 1 -C 6 )alkyl) 2 , or —O(C(R 11 ) 2 ) v ON((C 1 -C 6 )alkyl) 2 ;
R 6 represents independently for each occurrence H, alkyl, or —NHCH 2 CH═CH 2 ;
R 7 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 3 ;
R 8 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, or silyl;
R 9 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, alkylsulfonyl, alkylsulfoxide, arylsulfonyl, arylsulfoxide, or silyl;
R 10 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 11 represents independently for each occurrence hydrogen or alkyl;
n 1 and n 2 represent independently 0-21, inclusive;
m represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;
m 1 represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;
v represents independently for each occurrence 1, 2, 3, or 4;
w represents independently for each occurrence 1, 2, or 3 in accord with the rules of valence;
y represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;
M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
A 1 represents independently for each occurrence:
A 2 represents independently for each occurrence:
or -A 3 -A 4 -(A 5 ) w ;
A 3 represents independently for each occurrence
A 4 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, alkynyl diradical, alkylalkynyl diradical, aminoalkyl diradical, thioether, —C(O)—, —S(O)—, —S(O) 2 —, B 1 C(R) 2 B 2 , B 1 C(R)(B 2 ) 2 , B 1 C(B 2 ) 3 , B 1 N(R)(B 2 ), B 1 N(B 2 ) 2 , or has the formula:
B 1 is a bond between A 3 and A 4 ;
B 2 is a bond between A 4 and A 5 ;
R represents independently for each occurrence hydrogen or alkyl;
A 5 has the formula III:
wherein R 1-IIIA , R 1-IIIB ,R 2-III and R 3-III represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R;
A 6 is a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, —C(O)—, —S(O)—, —S(O) 2 —, or has the formula:
B 3 is a bond between A 6 and A 7 ;
B 4 is a bond between A 6 and A 1 ;
n 3 represents independently for each occurrence 1-15, inclusive;
n 4 is 1, 2, 3, 4, or 5 in accord with the rules of valence;
A 7 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 3 C(R) 2 B 5 , B 3 C(R)(B 5 ) 2 , B 3 C(B 5 ) 3 , B 3 N(R)(B 5 ), B 3 N(B 5 ) 2 , or has the formula:
p represents independently for each occurrence 1, 2, 3, or 4;
B 5 is a bond between A 5 and A 7 ;
A 8 has the formula:
wherein R 14 is H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or a bond between A 8 and A 9 ; or
X 2 is a bond or has the formula
B 6 is a bond between A 8 and A 1 ;
B 7 is a bond between A 8 and A 9 ;
A 9 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 7 C(R) 2 B 8 , B 7 C(R)(B 8 ) 2 , B 7 C(B 8 ) 3 , B 7 N(R)(B 8 ), B 7 N(B 8 ) 2 , or has the formula:
B 8 is a bond between A 5 and A 9 ;
A 10 is a bond or has the formula:
R 12 and R 13 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 9 ;
B 9 is a bond between A 10 and A 11 ;
B 10 is a bond between A 10 and O;
A 11 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 9 C(R) 2 B 11 , B 9 C(R)(B 11 ) 2 , B 9 C(B 11 ) 3 , B 9 N(R)(B 11 ), B 9 N(B 11 ) 2 , or has the formula:
B 11 is a bond between A 5 and A 11 ;
provided that at least one of X, X 1 , R 1 , or R 2 contain A 5 .
2. The double-stranded oligonucleotide of claim 1 , wherein R 1-IIIA is alkyl.
3. The double-stranded oligonucleotide of claim 1 , wherein R 3-III is alkyl.
4. The double-stranded oligonucleotide of claim 1 , wherein R 1-IIIA is methyl, R 1-IIIB is hydrogen, each R 2-III is hydrogen, and R 3-III is isobutyl.
5. The double-stranded oligonucleotide of claim 1 , wherein R 1-IIIA is methyl, R 1-IIIB is hydrogen, each R 2-III is hydrogen, R 3-III is isobutyl, w is 1, y is 1, A 6 is a bond, A 8 is B 6 —[C(R 14) 2 ] n 3 —B 6 ,n 3 is 1, R 14 is a bond between A 8 and A 9 , A 10 is a bond, A 7 is —CH 2 —, A 9 is a bond, and A 11 is —CH 2 —.
6. The double-stranded oligonucleotide of claim 1 , wherein said first strand and said second strand each contain at least one occurrence of A 5 .
7. The double-stranded oligonucleotide of claim 1 , wherein said first strand contains at least one occurrence of A 5 ; and said second strand does not.
8. The double-stranded oligonucleotide of claim 1 , wherein X is -A 6 -[A 7 -(A 5 ) w ] y .
9. The double-stranded oligonucleotide of claim 8 , wherein A 6 represents independently for each occurrence
and
wherein, A 7 independently represents for each occurrence
10. The double-stranded oligonucleotide of claim 9 , wherein A 7 is
wherein each R is H and m 1 is 6.
11. The double-stranded oligonucleotide of claim 1 , wherein X 1 is -A 8 -[A 9 -(A 5 ) w ] y .
12. The double-stranded oligonucleotide of claim 11 , wherein A 9 independently represents for each occurrence
13. The double-stranded oligonucleotide of claim 12 , wherein A 9 is
wherein each R is H and m 1 is 6.
14. The double-stranded oligonucleotide of claim 1 , wherein either R 1 or R 2 is —O-A 10 -[A 11 -(A 5 ) w ] y .
15. The double-stranded oligonucleotide of claim 14 , wherein A 10 represents independently for each occurrence
and wherein A 11 represents independently for each occurrence
16. The double-stranded oligonucleotide of claim 15 , wherein A 11 is
wherein each R is H and m 1 is 6.
17. A single-stranded oligonucleotide represented by formula IV:
wherein
X is H, —P(O)(OM) 2 , —P(O)(OM)-O—P(O)(OM) 2 , —P(O)(Oalkyl) 2 , —P(O)(Oalkyl)-O—P(O)(Oalkyl) 2 , or -A 6 -[A 7 -(A 5 ) w ] y ;
X 1 is
or -A 8 -[A 9 -(A 5 ) w ] y ;
Z 1 represents independently for each occurrence O or S;
Z 2 represents independently for each occurrence —OH, —OM, -Oalkyl, -Oaryl, -Oaralkyl, —SH, —SM, -Salkyl, -Saryl, -Saralkyl, —N(R 3 )R 4 , —(C(R 11 ) 2 ) m N(R 11 ) 2 , —N(R 11 )(C(R 11 ) 2 ) m N(R 11 ) 2 , or alkyl;
R 1 and R 2 represent independently for each occurrence H, OH, F, -Oalkyl, -Oallyl, —O(C(R 11 ) 2 ) v OR 11 , —O(C(R 11 ) 2 ) v SR 11 , —O(C(R 11 ) 2 ) v N(R 11 ) 2 , —O(C(R 11 ) 2 ) v C(O)N(R 11 ) 2 , —N(R 11 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C(R 11 ) 2 ) v N((C 1 -C 6 )alkyl) 2 , —O(C(R 11 ) 2 ) v ON((C 1 -C 6 )alkyl) 2 , or —O-A 10 -[A 11 -(A 5 ) w ] y ;
R 3 and R 4 represent H or alkyl; or R 3 and R 4 taken together form a 3-, 4-, 5-, 6-, or 7-membered ring;
R 5 represents independently for each occurrence H, OH, F, -Oalkyl, -Oallyl, —O(C(R 11 ) 2 ) v OR 11 , —O(C(R 11 ) 2 ) v SR 11 , —O(C(R 11 ) 2 ) v N(R 11 ) 2 , —O(C(R 11 ) 2 ) v C(O)N(R 11 ) 2 , —N(R 11 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v S(C 1 -C 6 )alkyl, —O(C(R 11 ) 2 ) v O(C(R 11 ) 2 ) v N((C 1 -C 6 )alkyl) 2 , or —O(C(R 11 ) 2 ) v ON((C 1 -C 6 )alkyl) 2 ;
R 6 represents independently for each occurrence H, alkyl, or —NHCH 2 CH═CH 2 ;
R 7 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 3 ;
R 8 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, or silyl;
R 9 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, alkylsulfonyl, alkylsulfoxide, arylsulfonyl, arylsulfoxide, or silyl;
R 10 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 11 represents independently for each occurrence hydrogen or alkyl;
n 1 and n 2 represent independently 0-21, inclusive;
m represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;
m 1 represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;
v represents independently for each occurrence 1, 2, 3, or 4;
w represents independently for each occurrence 1, 2, or 3 in accord with the rules of valence;
y represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;
M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
A 1 represents independently for each occurrence:
A 2 represents independently for each occurrence:
or -A 3 -A 4 -(A 5 ) w ;
A 3 represents independently for each occurrence
A 4 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, alkynyl diradical, alkylalkynyl diradical, aminoalkyl diradical, thioether, —C(O)—, —S(O)—, —S(O) 2 —, B 1 C(R) 2 B 2 , B 1 C(R)(B 2 ) 2 , B 1 C(B 2 ) 3 , B 1 N(R)(B 2 ), B 1 N(B 2 ) 2 , or has the formula:
B 1 is a bond between A 3 and A 4 ;
B 2 is a bond between A 4 and A 5 ;
R represents independently for each occurrence hydrogen or alkyl;
A 5 has the formula VI:
wherein R 1-VIA , R 1-VIB , R 2-VI and R 3-VI represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R;
A 6 is a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, —C(O)—, —S(O)—, —S(O) 2 —, or has the formula:
B 3 is a bond between A 6 and A 7 ;
B 4 is a bond between A 6 and A 1 ;
n 3 represents independently for each occurrence 1-15, inclusive;
n 4 is 1, 2, 3, 4, or 5 in accord with the rules of valence;
A 7 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 3 C(R) 2 B 5 , B 3 C(R)(B 5 ) 2 , B 3 C(B 5 ) 3 , B 3 N(R)(B 5 ), B 3 N(B 5 ) 2 , or has the formula:
p represents independently for each occurrence 1, 2, 3, or 4;
B 5 is a bond between A 5 and A 7 ;
A 8 has the formula:
wherein R 14 is H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or a bond between A 8 and A 9 ; or
X 2 is a bond or has the formula
B 6 is a bond between A 8 and A 1 ;
B 7 is a bond between A 8 and A 9 ;
A 9 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 7 C(R) 2 B 8 , B 7 C(R)(B 8 ) 2 , B 7 C(B 8 ) 3 , B 7 N(R)(B 8 ), B 7 N(B 8 ) 2 , or has the formula:
B 8 is a bond between A 5 and A 9 ;
A 10 is a bond or has the formula:
R 12 and R 13 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 9 ;
B 9 is a bond between A 10 and A 11 ;
B 10 is a bond between A 10 and O;
A 11 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 9 C(R) 2 B 11 , B 9 C(R)(B 11 ) 2 , B 9 C(B 11 ) 3 , B 9 N(R)(B 11 ), B 9 N(B 11 ) 2 , or has the formula:
B 11 is a bond between A 5 and A 11 ;
provided that at least one of X, X 1 , R 1 , or R 2 contain A 5 .
18. The single-stranded oligonucleotide of claim 17 , wherein R 1-VIA is alkyl.
19. The single-stranded oligonucleotide of claim 17 , wherein R 3-VI is alkyl.
20. The single-stranded oligonucleotide of claim 17 , wherein R 1-VIA is methyl, R 1-VIB is hydrogen, each R 2-VI is hydrogen, and R 3-VI is isobutyl.
21. The single-stranded oligonucleotide of claim 17 , wherein R 1-VIA is methyl, R 1-VIB is hydrogen, each R 2-VI is hydrogen, R 3-VI is isobutyl, w is 1, y is 1, A 6 is a bond, A 8 is B 6 —[C(R 14 ) 2 ] n 3 —B 6 , n 3 is 1, R 14 is a bond between A 8 and A 9 , A l0 is a bond, A 7 is —CH 2 —, A 9 is a bond, and A 11 is —CH 2 —.
22. The single-stranded oligonucleotide of claim 17 , wherein X is -A 6 -[A 7 -(A 5 ) w ] y .
23. The single-stranded oligonucleotide of claim 22 , wherein A 6 represents independently for each occurrence
and wherein, A 7 independently represents for each occurrence
24. The single-stranded oligonucleotide of claim 23 , wherein A 7 is
wherein each R is H and m 1 is 6.
25. The single-stranded oligonucleotide of claim 17 , wherein X 1 is -A 8 -[A 9 -(A 5 ) w ] y .
26. The single-stranded oligonucleotide of claim 25 , wherein A 9 independently represents for each occurrence
27. The single-stranded oligonucleotide of claim 26 , wherein A 9 is
wherein each R is H and m 1 is 6.
28. The single-stranded oligonucleotide of claim 17 , wherein either R 1 or R 2 is —O-A 10 -[A 11 -(A 5 ) w ] y .
29. The single-stranded oligonucleotide of claim 28 , wherein A 10 represents independently for each occurrence
and wherein A 11 represents independently for each occurrence
30. The single-stranded oligonucleotide of claim 29 , wherein A 11 is
wherein each R is H and m 1 is 6.