Functionally-modified oligonucleotides and subunits thereof

Patent metadata

Field	Value
Publication number	US-10344281-B2
Application number	US-201715700718-A
Country	US
Kind code	B2
Filing date	Sep 11, 2017
Priority date	Nov 18, 2011
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

Abstract

Functionally-modified 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.

First claim

What is claimed is:

1. A compound having the structure of Formula (I):

or a salt or isomer thereof,
wherein:
n is an integer from 1 to 50;
G 5 is halogen, OH, alkoxy, OSO 2 (alkyl), OSO 2 (aryl), or

each B is an independently selected base pair moiety;
each Y is independently O or NR 10 ; optionally, R 10 and X8e are bonded together form a ring;
each W is independently S or O;
Z 5 is -(L 11 )-(R 15 ), -(L 11 )-(L 15 )-(R 16 ), or -(L 11 )-(L 12 )-(R 17 );
L 11 is selected from:

wherein L 13 is selected from:

L 12 is a linker cleaveable under biological conditions selected from:
a) —(C 1 -C 10 alkylene)-OC(O)O—CH 2 O—;
b) —C(O)—(C 1 -C 10 alkylene)-OC(O)O—CH 2 O—;
c) —C(O)—(CH═CH)—C(O)O—CH 2 O—;
d) —(C 1 -C 10 alkylene)-S—S—CH 2 CH 2 O—; or
e) —C(O)—(C 1 -C 10 alkylene)-S—S—CH 2 CH 2 O—;
L 15 is divalent radical selected from C 1 -C 30 alkylene, C 3 -C 8 cycloalkylene, C 6 -C 30 arylene, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-, —(C 1 -C 30 alkylene)-C(═O)—, —(C 2 -C 30 alkoxy)-C(═O)—, -(3-18 membered heteroalkylene)-C(═O)—, —(C 3 -C 8 cycloalkylene)-C(═O)—, —(C 3 -C 8 cycloalkylene)-(C 1 -C 30 alkylene)-C(═O)—, —(C 1 -C 30 alkylene) (C 3 -C 8 cycloalkylene)-C(═O)—, —(C 6 -C 30 arylene)-C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-C(═O)—, —(C 1 -C 30 alkylene)-(C 6 -C 30 arylene)-C(═O)—, —(C 1 -C 30 alkylene)-O—C(═O)—, —(C 3 -C 8 cycloalkylene)-O—C(═O)—, —(C 7 -C 30 arylene)-O—C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-O—C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-O—C(═O)—, —C(═O)OR 21 , or —P(═O)(R 22 ) 2 ;
R 12 is an electron pair, with the provision that if R 13 is C 1 -C 30 alkyl, then R 12 is an electron pair, an N-oxide, or C 1 -C 6 alkyl;
each R 10 and R 13 is independently selected from hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 1 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 6 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 1 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, —C(═O)OR 21 , —C(═O)NHR 21 , or —P(═O)(R 22 ) 2 ;
R 15 is independently selected from a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 1 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 6 -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, 3-18 membered alkoxyalkylcarbonyl, —SO 2 R 21 , —C(═O)OR 21 , —P(═O)(OH) 2 or —P(═O)(R 22 ) 2 ;
R 16 is a solid support matrix suitable for solid phase synthesis of oligonucleotides;
R 17 is a drug, protein or toxin;
each R 21 is independently C 1 -C 30 alkyl, or a 3-18 membered alkoxyalkyl group;
each R 22 is independently an C 6 -C 12 aryloxy;
each R 23 is independently H or C 1 -C 6 alkyl; or optionally two R 23 groups join to form a 3- to 8-membered ring;
R 24 is a C 1 -C 6 alkylene;
Q is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8;

each X is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8 with the provision that at least one X is not X1;
wherein
X1 is N(CH 3 ) 2 ;
X2 is selected from:
a) —O-alkylene-CO 2 H;
b) —O-alkylene-CHN 4 ;
c) —N(R 1 )-alkylene-CO 2 H;
d) —N(R 1 )-alkylene-CHN 4 ;
e) -L1-CO-alkylene-CO 2 H;
f) -L1-CO-alkylene-CHN 4 ;
g) -L1-CO-alkenylene-CO 2 H;
h) -L1-CO-alkenylene-CHN 4 ;
i) -L1-CO-arylene-CO 2 H;
j) -L1-CO-arylene-CHN 4 ;
k) -L1-CONH-alkylene-CO 2 H;
l) -L1-CONH-alkylene-CHN 4 ;
m) -L1-CONH-arylene-CO 2 H;
n) -L1-CONH-arylene-CHN 4 ;
o) -L1-SO 2 -alkylene-CO 2 H;
p) -L1-SO 2 -alkylene-CHN 4 ;
q) -L1-SO 2 -arylene-CO 2 H;
r) -L1-SO 2 -arylene-CHN 4 ;
s) -L1-alkylene-CO 2 H;
t) -L1-alkylene-CHN 4 ;
u) -L1-arylene-CO 2 H;
v) -L1-arylene-CHN 4 ; and
w) a protected form of any of the above X2groups;

X3 is selected from:
a) -L1-alkyl;
b) -L1-heterocyclyl;
c) —O-alkylene-CNH—NH 2 ;
d) —N(R 1 )-alkylene-CNH—NH 2 ;
e) -L1-CNH—NH 2 ;
f) -L1-alkylene-CNH—NH 2 ;
g) -L1-arylene-CNH—NH 2 ;
h) -L1-CO-alkylene-CNH—NH 2 ;
i) -L1-CO-alkenylene-CNH—NH 2 ;
j) -L1-CO-arylene-CNH—NH 2 ;
k) -L1-CONH-alkylene-CNH—NH 2 ;
l) -L1-CONH-arylene-CNH—NH 2 ;
m) -L1-SO 2 -alkylene-CNH—NH 2 ;
n) -L1-SO 2 -arylene-CNH—NH 2 ;
o) —O-alkylene-N(R 1 ) 2 ;
p) —N(R 1 )-alkylene-N(R 1 ) 2 ;
q) -L1-N(R 1 ) 2 ;
r) -L1-alkylene-N(R 1 ) 2 ;
s) -L1-arylene-N(R 1 ) 2 ;
t) -L1-CO-alkylene-N(R 1 ) 2 ;
u) -L1-CO-alkenylene-N(R 1 ) 2 ;
v) -L1-CO-arylene-N(R 1 ) 2 ;
w) -L1-CONH-alkylene-N(R 1 ) 2 ;
x) -L1-CONH-arylene-N(R 1 ) 2 ;
y) -L1-SO 2 -alkylene-N(R 1 ) 2 ;
z) —O-alkylene-N(R 2 ) 3 ;
aa) —N(R 1 )-alkylene-N(R 2 ) 3 ;
bb) -L1-N(R 2 ) 3 ;
cc) -L1-alkylene-N(R 2 ) 3 ;
dd) -L1-arylene-N(R 2 ) 3 ;
ee) -L1-CO-alkylene-N(R 2 ) 3 ;
ff) -L1-CO-alkenylene-N(R 2 ) 3 ;
gg) -L1-CO-arylene-N(R 2 ) 3 ;
hh) -L1-CONH-alkylene-N(R 2 ) 3 ;
ii) -L1-CONH-arylene-N(R 2 ) 3 ;
jj) -L1-SO 2 -alkylene-N(R 2 ) 3 ;
kk) —O-alkylene-heterocyclyl;
ll) —N(R 1 )-alkylene-heterocyclyl;
mm) -L1-alkylene-heterocyclyl;
nn) -L1-arylene-heterocyclyl;
oo) -L1-CO-alkylene-heterocyclyl;
pp) -L1-CO-alkenylene-heterocyclyl;
qq) -L1-CO-arylene-heterocyclyl;
rr) -L1-CONH-alkylene-heterocyclyl;
ss) -L1-CONH-arylene-heterocyclyl;
tt) -L1-SO 2 -alkylene-heterocyclyl;
uu) —O-alkylene-N(O)(R 2 ) 2 ;
vv) —N(R 1 )-alkylene-N(O)(R 2 ) 2 ;
ww) -L1-N(O)(R 2 ) 2 ;
xx) -L1-alkylene-N(O)(R 2 ) 2 ;
yy) -L1-arylene-N(O)(R 2 ) 2 ;
zz) -L1-CO-alkylene-N(O)(R 2 ) 2 ;
aaa) -L1-CO-alkenylene-N(O)(R 2 ) 23 ;
bbb) -L1-CO-arylene-N(O)(R 2 ) 2 ;
ccc) -L1-CONH-alkylene-N(O)(R 2 ) 2 ;
ddd) -L1-CONH-arylene-N(O)(R 2 ) 2 ;
eee) -L1-SO 2 -alkylene-N(O)(R 2 ) 2 ;
fff) —O-alkylene-NH—CNH—NH 2 ;
ggg) —N(R 1 )-alkylene-NH—CNH—NH 2 ;
hhh) -L1-NH—CNH—NH 2 ;
iii) -L1-alkylene-NH—CNH—NH 2 ;
jjj) -L1-arylene-NH—CNH—NH 2 ;
kkk) -L1-CO-alkylene-NH—CNH—NH 2 ;
lll) -L1-CO-alkenylene-NH—CNH—NH 2 ;
mmm) -L1-CO-arylene-NH—CNH—NH 2 ;
nnn) -L1-CONH-alkylene-NH—CNH—NH 2 ;
ooo) -L1-CONH-arylene-NH—CNH—NH 2 ;
ppp) -L1-SO 2 -alkylene-NH—CNH—NH 2 ;
qqq) -L1-SO 2 -arylene-NH—CNH—NH 2 ; and
rrr) a protected form of any of the above X3 groups;

with the provision that if X1 is present as N(CH 3 ) 2 , and X7 is present as piperidinyl, then X3 is not

X4 is selected from:
a) —O-alkylene-aryl;
b) —N(R 1 )-aryl;
c) —N(R 1 )-alkylene-aryl;
d) -L1-CO-alkylene-aryl;
e) -L1-CO-alkenylene-aryl;
f) -L1-CO-arylene-aryl;
g) -L1-CONH-alkylene-aryl;
h) -L1-CONH-arylene-aryl;
i) -L1-SO 2 -alkylene-aryl;
j) -L1-SO 2 -arylene-aryl;
k) -L1-alkylene-aryl;
l) -L1-arylene-aryl;
m) —N(R 1 )-alkylene-N(R 1 )-aryl;
n) —N(R 1 )-alkylene-N(R 1 )CO-aryl;
o) —N(R 1 )-alkylene-N(R 1 )SO 2 -aryl;
p) —N(R 1 )-alkylene-N(R 1 )CH 2 -ary

Assignees

• Sarepta Therapeutics Inc

Inventors

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

Classifications

• C12N2310/353

  linked to the nucleic acid via an atom other than carbon · CPC title

• C12N2310/3513

  Protein; Peptide · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/3233

  Morpholino-type ring · CPC title