Cleavable linker-containing ionizable lipids and lipid carriers for therapeutic compositions
AssigneeFlagship Pioneering Innovations Vii, LLC
InventorsTimothy Ray Blake, Dean Peter Stamos
Life of this patent
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Abstract
The present disclosure relates to a lipid compound of formula (Ia) or (AL-GI): having various cleavable linkers defined by the variables Z1 and Z2 and Z10 and Z20. The present disclosure also relates to a lipid carrier or lipid nanoformulation employing the lipid compound, and the use of the lipid compound in a pharmaceutical composition as well as for a method of delivering an effector, e.g., a therapeutic agent.
Claims37
A compound having the structure of formula (I-w):
- or a salt thereof;
- wherein:
- RN2 is
- L1 and L2 are each independently (C1-C15)alkylene;
- Z10 and Z20 are each independently
- each of X1 and X2 is independently O, S, or N(R21);
- R20 is branched (C1-C15)alkyl or unbranched (C1-C15)alkyl;
- R21 is H, (C1-C5)alkyl, or (C3-C8)cycloalkyl;
- s is an integer from 1 to 4;
- in Z10, indicates the point of attachment to L1;
- in Z20, indicates the point of attachment to L2;
- and
- each of R22, R23, R24, and R25 is independently H, branched (C1-C15)alkyl, or unbranched (C1-C15)alkyl;
- provided that at least one of R22 and R23 is not H, and at least one of R24 and R25 is not H.
A compound having the structure of formula (I-w-4), (I-w-5), or (I-w-6):
- or a salt thereof;
- wherein:
- RN2 is —(CH2)m(NH)nQ2;
- Q2 is —OH, —SO2NH(alkyl), —SO2N(alkyl)2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkenyl;
- m is an integer from 2-3;
- n is an integer from 0-1;
- L1 and L2 are each independently (C1-C15)alkylene;
- each of X1 and X2 is independently O, S, or N(R21);
- R21 is H, (C1-C5)alkyl, or (C3-C8)cycloalkyl;
- and
- each of R22, R23, R24, and R25 is independently H, branched (C1-C15)alkyl, or unbranched (C1-C15)alkyl;
- provided that at least one of R22 and R23 is not H, and at least one of R24 and R25 is not H.
A compound having the structure of formula (I-w-7), (I-w-8), or (I-w-9):
- or a salt thereof:
- wherein:
- RN2 is —(CH2)m(NH)nQ2;
- Q2 is —OH, —SO2NH(alkyl), —SO2N(alkyl)2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkenyl;
- m is an integer from 2-3;
- n is an integer from 0-1;
- L1 and L2 are each independently (C1-C15)alkylene;
- s is an integer from 1 to 4;
- and
- each of R22, R23, R24, and R25 is independently H, branched (C1-C15)alkyl, or unbranched (C1-C15)alkyl;
- provided that at least one of R22 and R23 is not H, and at least one of R24 and R25 is not H.
A compound having the structure of formula (I-w-10), (I-w-11), (I-w-12), (I-w-13), (I-w-14), or (I-w-15):
- or a salt thereof:
- wherein:
- RN2 is —(CH2)m(NH)nQ2;
- Q2 is —OH, —SO2NH(alkyl), —SO2N(alkyl)2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkenyl;
- m is an integer from 2-3;
- n is an integer from 0-1;
- L1 and L2 are each independently (C1-C15)alkylene;
- R20 is branched (C1-C15)alkyl or unbranched (C1-C15)alkyl;
- R21 is H, (C1-C5)alkyl, or (C3-C8)cycloalkyl;
- and
- each of R22, R23, R24, and R25 is independently H, branched (C1-C15)alkyl, or unbranched (C1-C15)alkyl;
- provided that at least one of R22 and R23 is not H, and at least one of R24 and R25 is not H.
A compound having the structure of formula (Ia):
- or a salt thereof;
- wherein:
- RN2 is —(CH2)m(NH)nQ2,
- Q2 is —OH, —SO2NH(alkyl), —SO2N(alkyl)2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkenyl;
- m is an integer from 2-3;
- n is an integer from 0-1;
- L1 and L2 are each independently (C1-C15)alkylene;
- Z10 and Z20 are each independently
- each of X1 and X2 is independently O, S, or N(R21);
- R20 is branched (C1-C15)alkyl or unbranched (C1-C15)alkyl;
- R21 is H, (C1-C5)alkyl, or (C3-C8)cycloalkyl;
- s is an integer from 1 to 4;
- in Z10, indicates the point of attachment to L1;
- in Z20, indicates the point of attachment to L2;
- each of R22, R23, R24, and R25 is independently H, branched (C1-C15)alkyl, or unbranched (C1-C15)alkyl;
- provided that at least one of R22 and R23 is not H, and at least one of R24 and R25 is not H;
- wherein when Q2 is —OH, then at least one of (i) or (ii) applies:
- (i) at least one of Z10 and Z20 is
- or
- (ii) L1 and L2 are not identical.
A compound, or a salt thereof, having one of the following structures:
- wherein R=
- and each R27 is independent H, C1-C15 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
Dependencies are inferred from the claim text.