Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

Patent metadata

Field	Value
Publication number	US-10202602-B2
Application number	US-201615247584-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	May 28, 2010
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

Abstract

Oligonucleotide analogs 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.

First claim

The invention claimed is:

1. 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 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 0;
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 optionally substituted 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 (Ill):

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 , 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 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; and
B is, at each occurrence, independently 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; 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;
wherein if R 18 is R 20 , R 20 is, at each occurrence, guanidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 30 aryl, 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 ; or
wherein if R 19 is R 20 , R 20 is, at each occurrence, 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 .

2. The oligomer of claim 1 , wherein R 20 is C 7 -C 30 arylcarbonyl.

3. The oligomer of claim 1 , wherein R 20 is C 7 -C 30 aralkylcarbonyl.

4. The oligomer of claim 1 , wherein R 20 is C 6 -C 30 aryl.

5. The oligomer of claim 1 , wherein R 20 is C 1 -C 30 alkyl.

6. The oligomer of claim 1 , wherein R 20 is C 3 -C 30 alkylcarbonyl.

7. The oligomer of claim 1 , wherein R 20 is —C(═O)(CH 2 ) p SH or —C(═O)(CH 2 ) p SSHet, wherein p is an integer from 3 to 6 and Het is a heteroaryl.

8. The oligomer of claim 1 , wherein R 20 is C 3 -C 8 cycloalkylcarbonyl.

9. The oligomer of claim 1 , wherein R 20 is —C(═O)(CH 2 ) n CO 2 H, where n is 3 to 6.

10. The oligomer of claim 1 , wherein R 20 is guanidinyl.

11. The oligomer of claim 1 , wherein R 19 is —C(═O)OR 21 .

12. The oligomer of claim 1 , wherein R 20 is —P(═O)(R 22 ) 2 .

13. The oligomer of claim 1 , wherein R 18 is trimethylglycine.

14. The oligomer of claim 1 , wherein R 18 is a cell-penetrating peptide and R 19 is R 20 .

15. The oligomer of claim 1 , wherein R 19 is a cell-penetrating peptide and R 18 is R 20 .

16. The oligomer of claim 1 , wherein L 1 has the following structure (XXIX):

wherein R 24 is absent, H or C 1 -C 6 alkyl.

17. The oligomer of claim 1 , wherein R 29 has the following structure (XXX):

wherein R 25 is hydrogen or —SR 26 , wherein R 26 is hydrogen, C 1 -C 30 alkyl, heterocyclyl, aryl or heteroaryl, and q is an integer from 3 to 6.

18. The oligomer of claim 1 , wherein R 19 has the following structure:

19. The oligomer of claim 1 , wherein R 20 has one of the following structures:

Assignees

• Sarepta Therapeutics Inc

Inventors

• Hanson Gunnar J
• Rudolph Alexander Charles
• Cai Bao Zhong
• Zhou Ming
• Weller Dwight D

Classifications

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07F9/24

  Esteramides · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/12

  Antivirals · CPC title