Back to results
US 8,779,128 B2Granted
Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups
AssigneeSarepta Therapeutics, Inc.
InventorsGunnar J. Hanson, Charles Rudolph, Bao Zhong Cai, Ming Zhou, Dwight D. Weller
Life of this patent
Estimating the term…
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.
Claims32
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, tautomer or stereoisomer 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(CH3)2, —NR1R2, —OR3 or ;
- Y is, at each occurrence, independently O or —NR2,
- R1 is, at each occurrence, independently hydrogen or methyl;
- R2 is, at each occurrence, independently hydrogen or -LNR4R5R7;
- R3 is, at each occurrence, independently hydrogen or C1-C6 alkyl;
- R4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH2, —Z-L-NHC(═NH)NH2 or —[C(O)CHR′NH]mH, 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;
- R5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
- R6 is, at each occurrence, independently hydrogen or methyl;
- R7 is, at each occurrence, independently hydrogen C1-C6 alkyl or C1-C6 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 —NR8R9 or —OR3;
- and
- Y is, at each occurrence, independently O or —NR10,
- R8 is, at each occurrence, independently hydrogen or C2-C12 alkyl;
- R9 is, at each occurrence, independently hydrogen, C1-C12 alkyl, C1-C12 aralkyl or aryl;
- R10is, at each occurrence, independently hydrogen, C1-C12 alkyl or -LNR4R5R7;
- wherein R8 and R9 may join to form a 5-18 membered optionally substituted mono or bicyclic heterocycle or R8, R9 or R3 may join with R10 to form a 5-7 membered heterocycle, and wherein when X is 4-piperazino, X has the following structure (III):
- wherein:
- R11 is, at each occurrence, independently C2-C12 alkyl, C1-C12 aminoalkyl, C1-C12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl;
- and
- R is, at each occurrence, independently an electron pair, hydrogen or C1-C12 alkyl;
- and
- R12 is, at each occurrence, independently, hydrogen, C1-C12 alkyl, C1-C12 aminoalkyl, —NH2, —CONH2, —NR13R14R15 , C1C12 alkylcarbonyl, oxo, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR13 or C1-C12 alkoxy, wherein R13, R14 and R15 are, at each occurrence, independently C1-C12 alkyl;
- and
- wherein at least one of the intersubunit linkages is linkage (B) having the following structure (IV):
- wherein Z represents a 5-18 member optionally substituted mono or bicycic heterocycle;
- or
- wherein at least one of the intersubunit linkages is linkage (b) wherein X is —NR8R9 and R9 is C1-C12 aralkyl or aryl.
31 more elements
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, tautomer or stereoisomer thereof, and
- wherein for linkage (A):
- W is, at each occurrence, independently S or O;
- X is, at each occurrence, independently —N(CH3)2, —NR1R2, —OR3 or ;
- Y is, at each occurrence, independently O or —NR2,
- R1 is, at each occurrence, independently hydrogen or methyl;
- R2 is, at each occurrence, independently hydrogen or -LNR4R5R7;
- R3 is, at each occurrence, independently hydrogen or C1-C6 alkyl;
- R4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH2, —Z-L-NHC(═NH)NH2 or —[C(O)CHR′NH]mH, 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;
- R5 is, at each occurrence, independently hydrogen, methyl or an electron pair;
- R6 is, at each occurrence, independently hydrogen or methyl;
- R7 is, at each occurrence, independently hydrogen C1-C6 alkyl or C1-C6 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 —NR8R9 or —OR3;
- and
- Y is, at each occurrence, independently O or —NR ,
- R8 is, at each occurrence, independently hydrogen or C2-C12 alkyl;
- R9 is, at each occurrence, independently hydrogen, C1-C12 alkyl, C1-C12 aralkyl or aryl;
- R10 is, at each occurrence, independently hydrogen, C1-C12 alkyl or -LNR4R5R7;
- wherein R8 and R9 may join to form a 5-18 membered mono or bicyclic heterocycle or R8, R9 or R3 may join with R10 to form a 5-7 membered heterocycle, and wherein when X is 4-piparazino, X has the following structure (III):
- wherein:
- R10 is, at each occurrence, independently C2-C12 alkyl, C1-C12 aminoalkyl, C1-C12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl;
- and
- R11 is, at each occurrence, independently an electron pair, hydrogen or C1-C12 alkyl;
- R12 is, at each occurrence, independently, hydrogen, C1-C12 alkyl, C1-C12 aminoalkyl, —NH2, —CONH2, —NR13R14R15 C1C12 alkylcarbonyl, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl, guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR13 or C1-C12 alkoxy, wherein R13, R14 and R15 are, at each occurrence, independently C1-C12 alkyl;
- and
- R17 is, at each occurrence, independently absent, hydrogen or C1-C6 alkyl;
- R18 and R19 are, at each occurrence, independently absent, hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, C2-C30 alkylcarbonyl —C(═O)OR21 or R20;
- R20 is, at each occurrence, independently guanidinyl, heterocyclyl, C1-C30 alkyl, C3-C8 cycloalkyl;
- C6-C30 aryl, C7-C30 aralkyl, C3-C30 alkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkylalkylcarbonyl, C7-C30 arylcarbonyl, C7-C30 aralkylcarbonyl, C2-C30 alkyloxycarbonyl, C3-C8 cycloalkyloxycarbonyl, C7-C30 aryloxycarbonyl, C3-C30 aralkyloxycarbonyl, or —P(═O)(R22)2;
- R21 is C1-C30 alkyl comprising one or more oxygen or hydroxyl moieties or combinations thereof ;
- each R22 is independently C6-C12 aryloxy;
- Pi is, at ach occurrence independently a base-pairing moiety;
- L1 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;
- and
- wherein at least one of R18 or R19 is R20and provided that both of R17 and R18 are not absent;
- and
- wherein the oligomer comprises at least one linkage B having the following structure IV):
- wherein Z represents a 5-18 membered optionally substituted mono or heterocycle or
- wherein at east one of the intersubunit linkages is linkage (b) wherein X is —NR8R9 and R9 is C1-C 12 aralkyl or aryl.
41 more elements
Dependencies are inferred from the claim text.