Ionizable lipids for nucleic acid delivery
The present document describes compounds, or pharmaceutically acceptable salt thereof, of a core formula (I) Wherein R1 includes an amino group. These compounds are particularly useful in the formulation and in vivo and ex vivo delivery of nucleic acid and protein therapeutics for preparing and implementing T cell transfection, gene editing, cancer therapies, cancer prophylactics, and in the preparation of vaccines.
1 . A compound, or a pharmaceutically acceptable salt thereof, of formula (II):
wherein E 1 is selected from the group consisting of —O-δ 1 , —OC(O)O-δ 1 , —OC(O)-δ 1 , —OC(O)N(Q)-δ 1 , —OC(O)S-δ 1 , —C(O)N(Q)-δ 1 , —C(O)O-δ 1 , —N(Q)C(O)-δ 1 , —N(Q)C(O)O-δ 1 , —N(Q)C(O)S-δ 1 , and —N(Q)C(O)N(Q)-δ 1 ;
Q is H or a C 1 -C 5 alkyl; δ 1 designates the bond linked to R 1 ;
R 1 is selected from the group consisting of:
wherein:
R 3 and R 4 are each independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl; alternatively R 3 and R 4 may join to form a 4-6 membered ring containing oxygen (O) or up to 2 nitrogen (N), optionally substituted with 1-2 substituents, each independently selected from the group consisting of C 1 -C 6 alkyl, cyclopropyl, OH, and C 1 -C 3 alkoxy;
R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and 2-hydroxyethyl;
R 6 is H or a C 1 -C 6 alkyl;
a is 1, 2, 3, 4 or 5;
b and c are independently 0, 1, or 2;
c′ is 1, 2, 3, 4, or 5;
d is 1 or 2;
e is 0, 1, or 2;
each of E 2 is selected from the group consisting of —OC(O)-δ 2 , —OC(O)O-δ 2 , —OC(O)N(Q)-δ 2 , —O-δ 2 , —OCH 2 CH 2 O-δ 2 , and —OC(O)(CH 2 ) 6 C(O)O-δ 2 ; Q is H or a C 1 -C 5 alkyl; δ 2 designates the bond linked to R 2 ;
R 2 is
or has the formula —(CH 2 ) g -[L 3 -(CH 2 )] h —R 9 , wherein:
L 1 and L 2 are each, independently, a direct bond, —O-δ 3 , —CH 2 OC(O)-δ 3 , or —CH 2 O-δ 3 ; δ 3 designates the bond linked to the respective one of R 7 and R 8 ;
R 7 and R 8 are each independently a C 4 -C 10 alkyl, a C 4 -C 10 alkenyl or a C 4 -C 10 alkynyl;
f is 0, 1, 2, 3, 4, or 5;
L 3 is selected from the group consisting of
R 9 is H or a C 4 -C 8 alkyl;
g is an integer in the range of 1-18; and
h is 0, 1, 2, or 3.
2 . A compound, or a pharmaceutically acceptable salt thereof, of formula (II)
wherein E 1 is selected from the group consisting of —OC(O)O-δ 1 , —OC(O)-δ 1 , —OC(O)N(Q)-δ 1 , and —OC(O)S-δ 1 ; Q is H or a C 1 -C 5 alkyl; and δ 1 designates the bond linked to R 1 ;
R 1 is selected from the group consisting of:
wherein:
R 3 and R 4 are each independently selected from C 1 -C 6 alkyl; alternatively R 3 and R 4 may join to form a 5-6 membered ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents, each independently selected from C 1 -C 6 alkyl;
R 5 is a C 1 -C 6 alkyl or a C 3 -C 6 cycloalkyl;
R 6 is an H or a C 1 -C 6 alkyl;
a is 1, 2, 3, or 4;
b and c are independently 0, 1, or 2;
c′ is 2, 3, or 4;
d is 2;
e is 0 or 1;
each of E 2 is selected from the group consisting of —O-δ 2 , —OC(O)-δ 2 , —OCH 2 CH 2 O-δ 2 , and —OC(O)(CH 2 ) 6 C(O)O-δ 2 ; where δ 2 designates the bond linked to R 2 ;
R 2 is
or has the formula —(CH 2 ) g -[L 3 -(CH 2 )] h —R 9 , wherein:
L 1 and L 2 are each, independently, a direct bond, —O-δ 3 , —CH 2 OC(O)-δ 3 , or —CH 2 O-δ 3 ; δ 3 designates the bond linked to the respective one of R 7 and R 8 ;
R 7 and R 8 are each independently a C 4 -C 10 alkyl, a C 4 -C 10 alkenyl or a C 4 -C 10 alkynyl;
f is 0, 1, 2, 3, 4, or 5;
L 3 is selected from the group consisting of
R 9 is H or a C 4 -C 8 alkyl;
g is an integer in the range of 1-18; and
h is 0, 1, or 2.
3 . A compound, or a pharmaceutically acceptable salt thereof, of formula (II)
wherein E 1 is selected from the group consisting of —OC(O)O-δ 1 , —OC(O)-δ 1 , —OC(O)N(Q)-δ 1 , and —OC(O)S-δ 1 ; Q is H or a C 1 -C 5 alkyl; and δ 1 designates the bond linked to R 1 ;
R 1 is selected from the group consisting of:
wherein:
R 3 and R 4 are each independently selected from C 1 -C 6 alkyl; alternatively R 3 and R 4 may join to form a 5-6 membered ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents, each independently selected from C 1 -C 6 alkyl;
R 5 is a C 1 -C 6 alkyl or cyclopropyl;
R 6 is H or a C 1 -C 6 alkyl;
a is 1, 2, 3, or 4;
b is 0 or 1;
c is 0, 1, or 2;
c′ is 2, 3, or 4;
d is 2;
e is 1;
each of E 2 is selected from the group consisting of —O-δ 2 , —OC(O)-δ 2 , —OCH 2 CH 2 O-δ 2 , and —OC(O)(CH 2 ) 6 C(O)O-δ 2 ; where δ 2 designates the bond linked to R 2 ;
R 2 is
or has the formula —(CH 2 ) g -[L 3 -(CH 2 )] h —R 9 , wherein:
L 1 and L 2 are each a direct bond;
R 7 and R 8 are each independently selected from C 4 -C 10 alkyl;
f is 0 or 1;
L 3 is selected from the group consisting of
R 9 is H or a C 4 -C 8 alkyl;
g is an integer in the range of 1-18; and
h is 0, 1, or 2.
4 . A compound, or a pharmaceutically acceptable salt thereof, of formula (III)
wherein R 1 is selected from the group consisting of:
wherein:
R 3 and R 4 are each independently selected from C 1 -C 6 alkyl; alternatively R 3 and R 4 may join to form a 5-6 membered ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents, each independently selected from C 1 -C 6 alkyl;
R 5 is a C 1 -C 6 alkyl or cyclopropyl;
R 6 is H or a C 1 -C 6 alkyl;
a is 1, 2, 3, or 4;
b is 0 or 1;
c is 0, 1, or 2;
c′ is 2, 3, or 4;
dis 2;
e is 1;
each of E 2 is selected from the group consisting of —O-δ 2 , —OC(O)-δ 2 , —OCH 2 CH 2 O-δ 2 , and —OC(O)(CH 2 ) 6 C(O)O-δ 2 ; where δ 2 designates the bond linked to R 2 ;
R 2 is
or has the formula —(CH 2 ) g -[L 3 -(CH 2 )] h —R 9 , wherein:
L 1 and L 2 are each a direct bond;
R 7 and R 8 are each independently selected from C 4 -C 10 alkyl;
f is 0 or 1;
L 3 is selected from the group consisting of
R 9 is H or a C 4 -C 8 alkyl;
g is an integer in the range of 1-18; and
h is 0, 1, or 2.
5 . A compound according to any one of the following structures:
or a pharmaceutically acceptable salt thereof.
6 . A compound according to any one of the following structures:
or a pharmaceutically acceptable salt thereof.
7 . A lipid mix composition comprising any of the compounds of claim 1 , combined with one or more of a structural lipid, a sterol, or a stabilizing agent.
8 . The lipid mix composition of claim 7 , wherein the structural lipid comprises one or more structural lipids selected from the group consisting of distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoyl-phosphatidylethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), and sphingomyelins (SM) DSPC, DSPE, DPPC, DMPC, DOPC, POPC, DOPE and SM.
9 . The lipid mix composition of claim 7 , wherein the compound is present at about 10 Mol %-90 Mol %, the structural lipid is present at about 0-50 Mol %, the sterol is present at about 0-45 Mol %, and the stabilizing agent is present at 0-10 Mol %; and the total mol % of components of the lipid mix composition is 100 mol %.
10 . The lipid mix composition of claim 7 , wherein the compound is present at about 40 Mol %-60 Mol %, and the structural lipid is present at about 11-40 Mol %; and the total mol % of components of the lipid mix composition is 100 mol %.
11 . The lipid mix composition of claim 7 , wherein the compound is present at about 30 Mol % to 70 Mol %, wherein the total mol % of components of the lipid mix composition is 100 mol %.
12 . A lipid particle comprising the lipid mix composition of claim 7 and at least one therapeutic agent encapsulated therein.
13 . The compound of claim 1 , wherein one of the hydrogens is substituted with a halogen.
14 . The compound or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the experimental pKa of nanoparticles is in the range 5.6-7.1.
15 . A pharmaceutical composition comprising the compound of claim 1 , and at least one pharmaceutically acceptable carrier or excipient.
16 . The lipid mix composition of claim 7 , wherein the structural lipid includes DSPC, the sterol includes cholesterol, and the stabilizing agent includes polyoxyethylene (10) stearyl ether, and wherein the compound is present at 40 Mol %, DSPC is present at 20 Mol %, cholesterol is present at 37.5 Mol %, and polyoxyethylene (10) stearyl ether is present at 2.5 Mol %.
17 . The lipid mix composition of claim 7 , wherein the structural lipid includes DSPC, the sterol includes cholesterol, and the stabilizing agent includes PEG-DMG 2000, and wherein the compound is present at 40 to 47.5 Mol %, DSPC is present at 12.5 Mol %, cholesterol is present at 38.5 to 46 Mol %, and PEG-DMG 2000 is present at 1.5 Mol %.
18 . The lipid mix composition of claim 7 , wherein the structural lipid includes DOPE, the sterol includes cholesterol, and the stabilizing agent includes PEG-DMG 2000, and wherein the compound is present at 40 to 47.5 Mol %, DOPE is present at 12.5 Mol %, cholesterol is present at 38.5 to 46 Mol %, and PEG-DMG 2000 is present at 1.5 Mol %.
19 . The lipid mix composition of claim 7 , wherein the structural lipid is present at about 10 to 40 Mol % of the lipid mix composition.
20 . The lipid mix composition of claim 7 , wherein the sterol includes cholesterol, and the cholesterol is present at about 30 to 50 Mol % of the lipid mix composition.
21 . The lipid mix composition of claim 7 , wherein the stabilizing agent is present at about 0.1 to 3 Mol % of the lipid mix composition.
22 . The lipid mix composition of claim 7 , wherein the stabilizing agent is present at greater than 2.5 Mol % of the lipid mix composition.
23 . The lipid mix composition of claim 7 , wherein the stabilizing agent comprises polysorbate 80, Polyoxyethylene (40) stearate, polyoxyethylene (10) stearyl ether, a polyethylene glycol conjugated lipid, or combinations thereof.