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US 2026/0199239 A1Published application
Ionizable lipids with malonate tails
AssigneeModernaTX, Inc.
InventorEdward J. HENNESSY
Life of this patent
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Abstract
The present disclosure provides new ionizable lipids, lipid nanoparticle (LNP) compositions comprising the same, and methods of delivering therapeutic and/or prophylactic agents (e.g., mRNA) with the LNPs described herein. The ionizable lipids described herein comprise a central nitrogen atom bonded to (i) a head group; and (ii) two biodegradable, hydrophobic lipids tails, wherein at least one biodegradable lipid tail comprises a malonate moiety. Ionizable lipids described herein include compounds of Formula (I) and pharmaceutically acceptable salts thereof.
Claims102
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- T1 is selected from:
- RA and RB are each independently optionally substituted C4-20 alkylene, optionally substituted C4-20 alkenylene, or optionally substituted C4-20 alkynylene;
- R1 is optionally substituted, branched or unbranched C1-30 alkyl, optionally substituted, branched or unbranched C2-30 alkenyl, or optionally substituted, branched or unbranched C2-30 alkynyl;
- RM1, RM2, RM3, and RM4 are each independently optionally substituted, branched or unbranched C1-20 alkyl, optionally substituted, branched or unbranched C2-20 alkenyl, or optionally substituted, branched or unbranched C2-20 alkynyl;
- R4 is a head group selected from optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, and —Y1-Q;
- Y1 is optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, and optionally substituted C2-10 alkynylene;
- Q is optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, —ORO, —O(CH2)nN(RN)2, —O(CH2)nORO, —C(O)ORO, —OC(O)R, —OC(O)ORO, —CX3, —CX2H, —CXH2, —CN, —N(RN)2, —N(RN)(CH2)nN(RN)2, —N(RN)(CH2)nORO, —C(O)N(RN)2, —N(RN)C(O)R, —N(RN)C(O)N(RN)2, —N(RN)C(S)N(RN)2, —N(RN)C(═NR5)N(RN)2, —N(RN)C(═CHR5)N(RN)2, —C(═NR5)N(RN)2, —C(═NR5)R, —OC(O)N(RN)2, —N(RN)C(O)ORO, —C(R)N(RN)2C(O)ORO, —N(RN)S(O)2R, —N(RN)S(O)R, —S(O)2N(RN)2, —S(O)N(RN)2,
- each R is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, or optionally substituted C5-10 heteroaryl;
- each RO is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, optionally substituted C1-6 acyl, or an oxygen protecting group;
- each RN is independently hydrogen, —ORO, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, optionally substituted C1-6 acyl, or a nitrogen protecting group, or two RN attached to the same nitrogen atoms are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R5 is hydrogen, —CN, —NO2, —ORO, —S(O)2R, —S(O)2 (RN)2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, or optionally substituted C1-6 acyl, or optionally a nitrogen protecting group when attached to a nitrogen atom;
- R6 and R7 are each independently hydrogen, halogen, or optionally substituted C1-6 alkyl;
- each X is independently halogen;
- and
- n is 1, 2, 3, 4, or 5.
13 more elements
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- T1 is selected from:
- RA and RB are each independently optionally substituted C1-20 alkylene, optionally substituted C1-20 alkenylene, or optionally substituted C1-20 alkynylene;
- R1 is optionally substituted, branched or unbranched C1-30 alkyl, optionally substituted, branched or unbranched C2-30 alkenyl, or optionally substituted, branched or unbranched C2-30 alkynyl;
- RM1, RM2, RM3, and RM4 are each independently optionally substituted, branched or unbranched C1-20 alkyl, optionally substituted, branched or unbranched C2-20 alkenyl, or optionally substituted, branched or unbranched C2-20 alkynyl;
- R4 is a head group selected from optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, and —Y1-Q;
- Y1 is optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, and optionally substituted C2-10 alkynylene;
- Q is optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, —ORO, —O(CH2)nN(RN)2, —O(CH2)nORO, —C(O)ORO, —OC(O)R, —OC(O)ORO, —CX3, —CX2H, —CXH2, —CN, —N(RN)2, —N(RN)(CH2)nN(RN)2, —N(RN)(CH2)nORO, —C(O)N(RN)2, —N(RN)C(O)R, —N(RN)C(O)N(RN)2, —N(RN)C(S)N(RN)2, —N(RN)C(═NR5)N(RN)2, —N(RN)C(═CHR5)N(RN)2, —C(═NR5)N(RN)2, —C(═NR5)R, —OC(O)N(RN)2, —N(RN)C(O)ORO, —C(R)N(RN)2C(O)ORO, —N(RN)S(O)2R, —N(RN)S(O)R, —S(O)2N(RN)2, —S(O)N(RN)2,
- each R is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, or optionally substituted C5-10 heteroaryl;
- each RO is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, optionally substituted C1-6 acyl, or an oxygen protecting group;
- each RN is independently hydrogen, —ORO, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, optionally substituted C5-10 heteroaryl, optionally substituted C1-6 acyl, or a nitrogen protecting group, or two RN attached to the same nitrogen atoms are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R5 is hydrogen, —CN, —NO2, —ORO, —S(O)2R, —S(O)2 (RN)2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C3-8 heterocyclyl, or optionally substituted C5-10 heteroaryl, or optionally substituted C1-6 acyl, or optionally a nitrogen protecting group when attached to a nitrogen atom;
- R6 and R7 are each independently hydrogen, halogen, or optionally substituted C1-6 alkyl;
- each X is independently halogen;
- and
- n is 1, 2, 3, 4, or 5;
- provided that the total collective carbon atom content of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene groups of RA, RM1, and RM2, excluding optional substituents, is from 10-40 carbon atoms, inclusive;
- and/or
- provided that the total collective carbon atom content of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene groups of RB and R1, excluding optional substituents, is from 10-40 carbon atoms, inclusive.
16 more elements
The compound of any one of the preceding claims, where the compounds is selected from one of the following:
- Compound
- No.
- Structure
- M1
- M2
- M3
- M4
- M5
- M6
- M7
- M8
- M9
- M10
- M11
- M12
- M13
- M14
- M15
- M16
- M17
- and pharmaceutically acceptable salts thereof.
18 more elements
Dependencies are inferred from the claim text.