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US 2022/0396548 A1Published application
Ionizable lipids for nucleic acid delivery
AssigneeGlobal Life Sciences Solutions Canada ULC
InventorsNikita JAIN, Anitha THOMAS, Andrew William BROWN
Life of this patent
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Abstract
The present document describes compounds, or pharmaceutically acceptable salt thereof, of a core formula (I) where R1 features an amine group, particularly useful in the formulation of lipid particles including nucleic acid therapeutic agents, or proteins, or both, and for delivery of nucleic acid and protein therapeutics to cells in vivo or ex vivo, including anticancer and vaccine applications.
Claims22
A compound, or a pharmaceutically acceptable salt thereof, of formula (I):
- wherein:
- L1 is a direct bond or C1-C5 alkylene;
- E1 is selected from —O—, —OC(O)O—, —OC(O)—δ1, —OC(O)N(Q)-δ1, —OC(O)S-δ1, —N(Q)C(O)-δ1, —N(Q)C(O)O-δ1, —C(O)O-δ1, and —C(O)N(Q)-δ1;
- Q is H or C1-C5 alkyl;
- δ1 designates the bond linked to the R1 group;
- R1 is selected from:
- and wherein:
- R4 and R5 are each independently selected from group consisting of C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl;
- alternatively R4 and R5 may join to form 4-6 membered heterocyclic ring containing oxygen (O) or up to 2 nitrogen (N), optionally substituted with 1 or 2 substituents each independently selected from a C1-C6 alkyl, cyclopropyl, OH, and a C1-C3 alkoxy group;
- R6 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and a 2-hydroxyethyl group;
- R7 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, and a C2-C6 alkynyl group;
- a and c′ are independently 1, 2, 3, 4, or 5;
- b, c and e are independently 0, 1, or 2;
- d is 1, or 2;
- R2 is selected from H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, and
- L2 is a direct bond or δ2—(CR8R8′)k δ3 wherein R8 and R8′ are each independently H, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
- δ2 designates the bond linked to E2 group, and δ3 designates the bond linked to cyclopentyl scaffold described in formula (I);
- k is 1, 2, 3, 4, or 5;
- E2 is selected from —O—, —OC(O)O—, —OC(O)-δ4, —OC(O)N(Q)-δ4, —N(Q)C(O)-δ4, —N(Q)C(O)O-δ4, —C(O)N(Q)-δ4 or —C(O)O-δ4;
- Q is H or C1-C5 alkyl;
- where δ4 designates the bond linked to R3 group;
- R3 is selected from C8-C20 alkyl, C8-C20 alkenyl, C8-C20 alkynyl,
- wherein:
- f is 0, or 1;
- g is 1, or 2;
- g′ is 1, 2, 3, 4, or 5;
- h is 0, 1, 2, 3 or 4;
- R9 is a C6-C20 chain having the formula —(CH2)i-[L4-(CH2)]j—R12 wherein:
- L4 is selected from
- i is an integer in the range 6-20;
- j is 0, 1, 2, or 3;
- R12 is selected from H and C4-C8 alkyl;
- R9′ is selected from H, C4-C10 alkyl, C4-C10 alkenyl, and C4-C10 alkynyl;
- R10 and R10′ are each, independently selected from C4-C10 alkyl, C4-C10 alkenyl, and C4-C10 alkynyl;
- L3 is —OC(O)—δ5, —O-δ5, or a direct bond;
- δ5 designates the bond linked to R10 and R10′;
- and
- R11=R9, or has the formula:
35 more elements
A compound or a pharmaceutically acceptable salt thereof, of formula (I):
- wherein:
- L1 is a direct bond or C1-C5 alkylene;
- E1 is selected from —OC(O)O—, —OC(O)-δ1, —OC(O)N(Q)-δ1, —OC(O)S-δ1;
- Q is H or C1-C5 alkyl;
- δ1 designates the bond linked to the R1 group;
- R1 is selected from:
- wherein:
- R4 and R5 are each, independently selected from C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl;
- alternatively R4 and R5 may join to form 5-6 membered heterocyclic ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents each independently selected from a C1-C6 alkyl, and a cyclopropyl group;
- R6 is selected from C1-C6 alkyl, and C3-C6 cycloalkyl group;
- R7 is selected from H, and C1-C6 alkyl group;
- a is 1, 2, or 3;
- b and c are independently 0, 1, or 2;
- c′ is 2, 3, or 4;
- d is 1, or 2;
- e is 0, or 1;
- R2 is selected from H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and H;
- L2 is a direct bond or δ2—(CR8R8′)k δ3 wherein R8 and R8′ are each independently H, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
- δ2 designates the bond linked to E2 group and δ3 designates the bond linked to cyclopentyl scaffold described in formula (I);
- k is 1;
- E2 is selected from —O—, —OC(O)O—, —OC(O)-δ4, —OC(O)N(Q)-δ4, —C(O)N(Q)-δ4 or —C(O)O-δ4;
- Q is H or C1-C5 alkyl;
- where 64 designates the bond linked to R3 group;
- R3 is selected from C5-C20 alkyl, C8-C20 alkenyl, C5-C20 alkynyl,
- wherein:
- f and h are each 0;
- g is 1 or 2;
- R9 is a C6-C20 chain having the formula —(CH2)i-[L4-(CH2)]jR12, wherein:
- L4 is selected from
- i is an integer from 6-20;
- j is 0, 1, or 2;
- R12 is selected from H, and C4-C8 alkyl group;
- R9′ is selected from H, and C4-C10 alkyl;
- R10 and R10′ are each, independently selected from C4-C10 alkyl, C4-C10 alkenyl, and C4-C10 alkynyl;
- L3 is —OC(O)—δ5, or a direct bond;
- δ5 designates the bond linked to R10 and R10′;
- R11 is the same as R9.
34 more elements
A compound, or a pharmaceutically acceptable salt thereof, of formula (II):
- wherein:
- L1 is a direct bond;
- E1 is selected from —OC(O)O—, —OC(O)-δ1, —OC(O)N(Q)-δ1, —OC(O)S-δ1;
- Q is H or C1-C5 alkyl;
- 61 designates the bond linked to the R1 group;
- R1 is selected from
- wherein:
- R4 and R5 are each, independently selected from C1-C6 alkyl;
- alternatively R4 and R5 may join to form 5-6 membered heterocyclic ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents each independently selected from a C1-C6 alkyl;
- R6 is selected from C1-C6 alkyl, and cyclopropyl group;
- R7 is selected from H, and C1-C6 alkyl group;
- a is 1, 2, or 3;
- b is 0, or 1;
- c is 0, 1, or 2;
- c′ is 2, 3, or 4;
- d is 2;
- e is 1;
- R2 is selected from H, C1-C5 alkyl, C2-C5 alkenyl, and
- R3 is selected from:
- wherein:
- f and h are each 0;
- g is 1, or 2;
- R9 is a C6-C20 chain having the formula —(CH2)i-[L4-(CH2)]j—R12, wherein:
- L4 is selected from
- i is an integer in the range 6-20;
- j is 0, 1, or 2;
- R12 is selected from H and C4-C8 alkyl group;
- R9′ is selected from H, and C4-C10 alkyl;
- R10 and R10′ are each, independently selected from C4-C10 alkyl;
- L3 is a direct bond;
- R13 is the same as R11.
28 more elements
A compound, or a pharmaceutically acceptable salt thereof, of formula (III):
- wherein:
- R1 is selected from:
- wherein:
- R4 and R5 are each, independently selected from C1-C6 alkyl;
- alternatively, R4 and R5 may join to form a 5-6 membered heterocyclic ring containing up to 2 nitrogen (N), optionally substituted with 1-2 substituents each independently selected from C1-C6 alkyl;
- R6 is selected from C1-C6 alkyl, and a cyclopropyl group;
- R7 is selected from H, and a C1-C6 alkyl group;
- a is 1, 2, or 3;
- b is 0, or 1;
- c is 0, 1, or 2;
- c′ is 2, 3, or 4;
- d is 2;
- e is 1;
- R2 is selected from H, C1-C5 alkyl, C2-C5 alkenyl, and
- R3 is selected from:
- wherein:
- f and h are 0;
- g is 1 or 2;
- R9 is a C6-C20 chain having the formula —(CH2)i [L4-(CH2)]j—R12, wherein:
- L4 is selected from
- i is an integer in the range 6-20;
- j is 0, 1, or 2;
- R12 is selected from H and C4-C8 alkyl group;
- R9′ is selected from H, and C4-C10 alkyl;
- R10 and R10′ are each, independently selected from C4-C10 alkyl;
- L3 is a direct bond;
- R11 is the same as R9.
24 more elements
5-9. (canceled)
A compound selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of
14-15. (canceled)
18-21. (canceled)
(canceled)
28-39. (canceled)
41-45. (canceled)
Dependencies are inferred from the claim text.