Amino alcohol cationic lipids for oligonucleotide delivery
View Patent ↗The instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that is more efficacious than traditional cationic lipids. The present invention employs amino alcohols to enhance the efficiency of in vivo delivery of siRNA.
1. A lipid of Formula A:
wherein:
R 1 and R 2 are independently selected from H, (C 1 -C 6 )alkyl, heterocyclyl and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R′, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R′;
R 3 is selected from H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with one to three substituents selected from R′, or R 3 can be taken together with R 1 to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R′;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO 2 R″ and CON(R″) 2 ;
R″ is independently selected from H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with halogen and OH;
L 1 is C 4 -C 22 alkenyl, said alkenyl is optionally substituted with R′; and
L 2 is selected from C 4 -C 22 alkyl and C 4 -C 22 alkenyl, said alkyl and alkenyl are optionally substituted with R′;
or any pharmaceutically acceptable salt or stereoisomer thereof.
2. A lipid of Formula A according to claim 1 , wherein:
R 1 and R 2 are each H;
R 3 is H;
L 1 is C 4 -C 22 alkenyl; and
L 2 is selected from C 4 -C 22 alkyl and C 4 -C 22 alkenyl;
or any pharmaceutically acceptable salt or stereoisomer thereof.
3. A lipid which is selected from:
2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl)}propan-1-ol (Compound 1);
2-amino-3-[(9Z)-octadec-9-en-1-yloxy]-2-{[(9Z)-octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 2);
2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-[(octyloxy)methyl]propan-1-ol (Compound 3); and
2-(dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 4) or any pharmaceutically acceptable salt or stereoisomer thereof.
4. A lipid particle comprising a lipid according to claim 1 .