US 11,858,884 B2
Compositions and methods for modulating gene or gene product in cells
Daniel J. Siegwart, Dallas, TX (US); and Kejin Zhou, Dallas, TX (US)
Assigned to The Board of Regents of The University of Texas System, Austin, TX (US)
Filed by The Board of Regents of The University of Texas System, Austin, TX (US)
Filed on Dec. 30, 2021, as Appl. No. 17/566,666.
Application 17/566,666 is a continuation of application No. 15/265,064, filed on Sep. 14, 2016, granted, now 11,247,968.
Claims priority of provisional application 62/218,412, filed on Sep. 14, 2015.
Prior Publication US 2022/0257792 A1, Aug. 18, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07C 321/14 (2006.01); A61K 9/51 (2006.01); A61K 31/7105 (2006.01); A61K 31/7125 (2006.01); A61K 47/59 (2017.01); A61K 47/60 (2017.01); A61K 47/69 (2017.01); A61K 48/00 (2006.01); C07C 323/52 (2006.01); C07D 295/15 (2006.01); A61K 47/20 (2006.01); A61K 47/22 (2006.01)
CPC C07C 321/14 (2013.01) [A61K 9/513 (2013.01); A61K 9/5146 (2013.01); A61K 31/7105 (2013.01); A61K 31/7125 (2013.01); A61K 47/20 (2013.01); A61K 47/22 (2013.01); A61K 47/59 (2017.08); A61K 47/60 (2017.08); A61K 47/6931 (2017.08); A61K 48/0041 (2013.01); C07C 323/52 (2013.01); C07D 295/15 (2013.01)] 44 Claims
 
1. A method for delivering a nucleic acid to a cell of a subject, the method comprising administering to said subject said nucleic acid, wherein said nucleic acid is formulated with a nanoparticle comprising a compound having the structure of Formula (I):
Core-Repeating Unit-Terminating Group,
or a pharmaceutically acceptable salt thereof,
wherein:
the core is linked to two to six repeating units, and each repeating unit is linked to a nitrogen of the core; wherein:
the core corresponds to the structure of Formula (II):

OG Complex Work Unit Chemistry
wherein, in Formula (II):
X1 is optionally substituted dialkylamino(C≤12), optionally substituted heterocycloalkyl(C≤12), or optionally substituted heteroaryl(C≤12);
R1 is amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), or optionally substituted dialkylamino(C≤12); and
a is 1, 2, 3, 4, 5, or 6; or
alternatively, the core corresponds to the structure of Formula (III):

OG Complex Work Unit Chemistry
wherein, in Formula (III):
X2 is N(R5)y, wherein:
R5 is hydrogen or optionally substituted alkyl(C≤18); and
y is 0, 1, or 2, provided that the sum of y and z is 3;
R2 is amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), or optionally substituted dialkylamino(C≤12);
b is 1, 2, 3, 4, 5, or 6; and
z is 1, 2, 3; provided that the sum of z and y is 3; or
alternatively, the core corresponds to the structure of Formula (IV):

OG Complex Work Unit Chemistry
wherein, in Formula (IV):
X3 is selected from —NR6—, —O—, optionally substituted alkylaminodiyl(C≤8), optionally substituted alkoxydiyl(C≤8), optionally substituted arenediyl(C≤8), optionally substituted heteroarenediyl(C≤8), and optionally substituted heterocycloalkanediyl(C≤8),
wherein R6 is hydrogen or optionally substituted alkyl(C≤8);
R3 and R4 are each independently amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), optionally substituted dialkylamino(C≤12), or a group of the formula:

OG Complex Work Unit Chemistry
wherein:
e is 1, 2, or 3; and
Rc and Rd are each independently hydrogen, or optionally substituted alkyl(C≤6);
and
c and d are each independently 1, 2, 3, 4, 5, or 6;
each repeating unit
is a degradable diacyl group of Formula (VII):

OG Complex Work Unit Chemistry
wherein, in Formula (VII):
A1 and A2 are each independently —O—; and
Y3 is optionally substituted alkanediyl(C≤12), optionally substituted alkenediyl(C≤12), or optionally substituted arenediyl(C≤12);
R9 is optionally substituted alkyl(C≤8); wherein the core contains at least one nitrogen atom
and
each terminating group has the structure of Formula (VIII):

OG Complex Work Unit Chemistry
wherein, in Formula (VIII):
Y4 is alkanediyl(C≤18) optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —F, —Cl, —Br, —I, —SH, —OCH3, —OCH2CH3, —SCH3, and —OC(O)CH3; and
R10 is hydrogen,
wherein a protein expressed by said nucleic acid is detected in a cell of the subject following said administration of said nucleic acid formulated with said nanoparticle.