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US 12,503,432 B2Granted
Ionizable lipids for nucleic acid delivery
AssigneeGlobal Life Sciences Solutions Canada ULC
InventorsNikita Jain, Anitha Thomas, Andrew William Brown
Life of this patent
Estimating the term…
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.
Claims16
A compound, or a pharmaceutically acceptable salt thereof, of formula (I):
- wherein:
- L1 is a direct bond or C1-C5 alkylene;
- E1 is —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, or —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 C1-C6 alkyl, C2-C6 alkenyl, or 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 that are each independently C1-C6 alkyl, cyclopropyl, OH, and C1-C3 alkoxy;
- R6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 2-hydroxyethyl;
- R7 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
- a and c′ are each independently 1, 2, 3, 4, or 5;
- b, c and e are each independently 0, 1, or 2;
- d is 1, or 2;
- R2 is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or
- 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 —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 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 H or C4-C8 alkyl;
- R9′ is H, C4-C10 alkyl, C4-C10 alkenyl, or C4-C10 alkynyl;
- R10 and R10′ are each independently C4-C10 alkyl, C4-C10 alkenyl, or 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:
36 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 —OC(O)O—, —OC(O)-δ1, —OC(O)N(Q)-δ1 or —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 C1-C6 alkyl, C2-C6 alkenyl, 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 or 2 substituents that are each independently C1-C6 alkyl, or cyclopropyl;
- R6 is C1-C6 alkyl or C3-C6 cycloalkyl;
- R7 is H or C1-C6 alkyl;
- a is 1, 2, or 3;
- b and c are each independently 0, 1, or 2;
- c′ is 2, 3, or 4;
- d is 1 or 2;
- e is 0 or 1;
- R2 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or
- 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 δ4 designates the bond linked to R3 group;
- R3 is selected from C8-C20 alkyl, C8-C20 alkenyl, C8-C20 alkynyl,
- wherein:
- f and h are each 0;
- g is 1 or 2;
- 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 from 6-20;
- j is 0, 1, or 2;
- R12 is H or C4-C8 alkyl group;
- R9′ is H or C4-C10 alkyl;
- R10 and R10′ are each independently C4-C10 alkyl, C4-C10 alkenyl, or C4-C10 alkynyl;
- L3 is —OC(O)-δ5 or a direct bond;
- δ5 designates the bond linked to R10 and R10′;
- and
- R11 is the same as R9.
36 more elements
Dependencies are inferred from the claim text.