US2021139897A1PendingUtilityA1
Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups
Est. expiryMay 28, 2030(~3.8 yrs left)· nominal 20-yr term from priority
Y02P20/55A61P 31/04C07F 9/222A61P 29/00C12N 15/1131C07F 9/65846A61K 31/496C07H 21/02C07F 9/59C07F 9/65583A61P 13/12C07D 295/108C07F 9/26C12N 2310/11A61K 31/5377A61P 21/00C07F 9/22C07F 9/6561A61P 31/16C07H 1/00A61P 31/12C07F 9/572C07D 265/30C12N 15/113C12N 2310/3233A61P 21/04C12N 2310/3513C07F 9/6544A61P 25/00C07F 9/60A61P 21/02C07H 21/00C07F 9/24
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Claims
Abstract
Oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′-end of one morpholino ring structure to a 5′-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein the intersubunit linkages have the following general structure (I):
or a salt or isomer thereof, and wherein each of the intersubunit linkages (I) are independently linkage (A) or linkage (B):
wherein for linkage (A):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently-N(CH 3 ) 2 , —NR 1 R 2 , —OR 3 or;
Y is, at each occurrence, independently O or —NR 2 ,
R 1 is, at each occurrence, independently hydrogen or methyl;
R 2 is, at each occurrence, independently hydrogen or -LNR 4 R 5 R 7 ;
R 3 is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl;
R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —Z-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
R 5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
R 6 is, at each occurrence, independently hydrogen or methyl;
R 7 is, at each occurrence, independently hydrogen C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl;
L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof; and
wherein for linkage (B):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently —NR 8 R 9 or —OR 3 ; and
Y is, at each occurrence, independently O or —NR 10 ,
R 8 is, at each occurrence, independently hydrogen or C 2 -C 12 alkyl;
R 9 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;
R 10 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl or -LNR 4 R 5 R 7 ;
wherein R 8 and R 9 may join to form a 5-18 membered mono or bicyclic heterocycle or R 8 , R 9 or R 3 may join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piperazino, X has the following structure (III):
wherein:
R 11 is, at each occurrence, independently C 2 -C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl; and
R is, at each occurrence, independently an electron pair, hydrogen or C 1 -C 12 alkyl; and
R 12 is, at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 , —NR 13 R 14 R 15 , C 1 -C 12 alkylcarbonyl, oxo, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl;
wherein the oligomer sequence is selected from SEQ ID Nos.: 1-55; and
wherein at least one of the intersubunit linkages is linkage (B).
2 . The oligomer of claim 1 , wherein at least one of the morpholino ring structures has the following structure (i):
wherein B is, at each occurrence, independently a base-pairing moiety.
3 - 4 . (canceled)
5 . The oligomer of claim 1 , wherein W and Y are each O at each occurrence.
6 - 19 . (canceled)
20 . The oligomer of claim 1 , wherein at least one linkage (B) has one of the following structures:
21 - 24 . (canceled)
25 . The oligomer of claim 1 , wherein the oligomer has the following structure (XVII):
or a salt or isomer thereof, wherein:
R 17 is, at each occurrence, independently absent, hydrogen or C 1 -C 6 alkyl;
R 18 and R 19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C 2 -C 30 alkylcarbonyl, —C(═O)OR 21 or R 20 ;
R 20 is, at each occurrence, independently guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 3 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 7 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, or —P(═O)(R 22 ) 2 ;
R 21 is C 1 -C 30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof;
each R 22 is independently C 6 -C 12 aryloxy
B is a base-pairing moiety;
L 1 is an optional linker up to 18 atoms in length comprising bonds selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate and phosphodiester;
x is an integer of 0 or greater; and
provided that both of R 17 and R 18 are not absent.
26 . The oligomer of claim 25 , wherein at least one of R 18 or R 19 is R 20 .
27 - 28 . (canceled)
29 . The oligomer of claim 25 , wherein R 19 is piperizinyl or
30 . An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages of type (A), (B), or combinations thereof, wherein each morpholino ring structure supports a base-pairing moiety, such that the oligomer compound can bind in a sequence-specific manner to a target nucleic acid, and wherein the oligomer comprises a 3′ terminus, a 5′ terminus and has the following structure (XVII):
or a salt or isomer thereof, and
wherein for linkage (A):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently —N(CH 3 ) 2 , —NR 1 R 2 , —OR 3 or;
Y is, at each occurrence, independently O or —NR 2 ,
R 1 is, at each occurrence, independently hydrogen or methyl;
R 2 is, at each occurrence, independently hydrogen or -LNR 4 R 5 R 7 ;
R 3 is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl;
R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —Z-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
R 5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
R 6 is, at each occurrence, independently hydrogen or methyl;
R 7 is, at each occurrence, independently hydrogen C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl;
L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof; and
wherein for linkage (B):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently —NR 8 R 9 or —OR 3 ; and
Y is, at each occurrence, independently O or —NR 10 ,
R 8 is, at each occurrence, independently hydrogen or C 2 -C 12 alkyl;
R 9 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;
R 10 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl or -LNR 4 R 5 R 7 ;
wherein R 8 and R 9 may join to form a 5-18 membered mono or bicyclic heterocycle or R 8 , R 9 or R 3 may join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piparazino, X has the following structure (III):
wherein:
R 10 is, at each occurrence, independently C 2 -C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl; and
R 11 is, at each occurrence, independently an electron pair, hydrogen or C 1 -C 12 alkyl;
R 12 is, at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 , —NR 13 R 14 R 15 , C 1 -C 12 alkylcarbonyl, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl; and
R 17 is, at each occurrence, independently absent, hydrogen or C 1 -C 6 alkyl;
R 18 and R 19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C 2 -C 30 alkylcarbonyl, —C(═O)OR 21 or R 20 ;
R 20 is, at each occurrence, independently guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 3 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 7 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, or —P(═O)(R 22 ) 2 ;
R 21 is C 1 -C 30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof;
each R 22 is independently C 6 -C 12 aryloxy;
B is a base-pairing moiety;
L 1 is an optional linker up to 18 atoms in length comprising bonds selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, disulfide, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate, piperazine and phosphodiester;
x is an integer of 0 or greater;
wherein the oligomer sequence is selected from SEQ ID Nos.: 1-55; and
wherein at least one of R 18 or R 19 is R 20 and provided that both of R 17 and R 18 are not absent.
31 - 33 . (canceled)
34 . The oligomer of claim 30 , wherein R 20 is C 7 -C 30 aralkylcarbonyl.
35 - 61 . (canceled)
62 . The oligomer of claim 30 , wherein R 18 is a cell-penetrating peptide and R 19 is R 20 .
63 . The oligomer of claim 30 , wherein R 19 is a cell-penetrating peptide and R 18 is R 20 .
64 - 66 . (canceled)
67 . The oligomer of claim 30 , wherein L 1 has the following structure (XXIX):
wherein R 24 is absent, H or C 1 -C 6 alkyl.
68 - 70 . (canceled)
71 . The oligomer of claim 30 , wherein R 19 has the following structure:
72 - 81 . (canceled)
82 . An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages of type (A), (B), or combinations thereof, wherein each morpholino ring structure supports a base-pairing moiety, such that the oligomer compound can bind in a sequence-specific manner to a target nucleic acid, and wherein the oligomer comprises a 3′ terminus, a 5′ terminus and has the following structure (XVII):
or a salt or isomer thereof, and
wherein for linkage (A):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently —N(CH 3 ) 2 , —NR 1 R 2 , —OR 3 or;
Y is, at each occurrence, independently O or —NR 2 ,
R 1 is, at each occurrence, independently hydrogen or methyl;
R 2 is, at each occurrence, independently hydrogen or -LNR 4 R 5 R 7 ;
R 3 is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl;
R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —Z-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where Z is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
R 5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
R 6 is, at each occurrence, independently hydrogen or methyl;
R 7 is, at each occurrence, independently hydrogen C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl;
L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy or alkylamino groups, or combinations thereof; and
wherein for linkage (B):
W is, at each occurrence, independently S or O;
X is, at each occurrence, independently —NR 8 R 9 or —OR 3 ; and
Y is, at each occurrence, independently O or —NR 10 ,
R 8 is, at each occurrence, independently hydrogen or C 2 -C 12 alkyl;
R 9 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;
R 10 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl or -LNR 4 R 5 R 7 ;
wherein R 8 and R 9 may join to form a 5-18 membered mono or bicyclic heterocycle or R 8 , R 9 or R 3 may join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piparazino, X has the following structure (III):
wherein:
R 10 is, at each occurrence, independently C 2 -C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl; and
R 11 is, at each occurrence, independently an electron pair, hydrogen or C 1 -C 12 alkyl;
R 12 is, at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 , —NR 13 R 14 R 15 , C 1 -C 12 alkylcarbonyl, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl; and
R 17 is, at each occurrence, independently absent, hydrogen or C 1 -C 6 alkyl;
R 18 and R 19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C 2 -C 30 alkylcarbonyl, —C(═O)OR 21 or R 20 ;
R 20 is, at each occurrence, independently guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 3 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 7 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, or —P(═O)(R 22 ) 2 ;
R 21 is C 1 -C 30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof;
each R 22 is independently C 6 -C 12 aryloxy;
B is a base-pairing moiety;
L 1 is an optional linker up to 18 atoms in length comprising bonds selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, disulfide, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate, piperazine and phosphodiester;
x is an integer of 0 or greater;
wherein the cell-penetrating peptide sequence is selected from SEQ ID Nos.: 56-70; and
wherein at least one of R 18 or R 19 is R 20 and provided that both of R 17 and R 18 are not absent.
83 . The oligomer of claim 82 , wherein R 20 is C 7 -C 30 aralkylcarbonyl.
84 . The oligomer of claim 82 , wherein R 18 is a cell-penetrating peptide and R 19 is R 20 .
85 . The oligomer of claim 82 , wherein R 19 is a cell-penetrating peptide and R 18 is R 20 .
86 . The oligomer of claim 82 , wherein L 1 has the following structure (XXIX):
wherein R 24 is absent, H or C 1 -C 6 alkyl.
87 . The oligomer of claim 82 , wherein R 19 has the following structure:Join the waitlist — get patent alerts
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