Lipids for delivery of charged material, formulations thereof and method for making same

A lipid comprising a branched lipid moiety L having the structure of Formula I:

• A-(V)m—Z-L, wherein Formula I:
• A is a head group that is ionizable, permanently charged or zwitterionic;
• (V)m is an optional —(CR1R2)m-, and m is 1 to 10 or 2 to 6, wherein R1 and R2 are each independently:
• hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or a heterocycle;
• and
• Z-L has a structure of Formula II, IIa or IIb below,
• and wherein L is a hydrocarbon structure and has a moiety of Formula IIIc below:
• wherein a scaffold carbon chain of L is denoted by L1′-L1″-CH—[CH2]q—CH3, and wherein
• the total number of carbon atoms in the L carbon backbone is 10 to 30;
• L1′ is a linear hydrocarbon chain having no heteroatoms and has 5-12 carbon atoms and 0-3 cis or trans double bonds;
• L1″ is a carbon atom;
• each X1 is independently selected from an ether, ester and carbamate group;
• L1′″ is a carbon backbone portion of the scaffold carbon chain L and is depicted by G1-CH—[CH2]q—CH3 and wherein G′ is a hydrocarbon chain of 0-4 carbon atoms, optionally having one cis or trans double bond;
• wherein n is 0 to 4;
• wherein p is 1 to 4;
• wherein n+p is 1 to 4;
• q is 0 to 20;
• wherein each S and L1″″ is a hydrocarbon side chain and is independently:
• (a) a linear or branched terminating hydrocarbon chain with 0 to 5 cis or trans C═C and 2 to 30 carbon atoms and conjugated to one of a respective X1 at any carbon atom in its hydrocarbon chain thereof;
• or
• (b) a branched hydrocarbon structure of Formula IIIc,
• wherein each one of the L1″″ and S hydrocarbon chains in the lipid moiety is optionally substituted with a heteroatom, with the proviso that no more than 2 heteroatoms are substituted in the hydrocarbon chains,
• Formula II linear linker structure:
• X1-Lb,
• wherein X1 is optional and X1 is selected from an ether, ester and carbamate group;
• and
• Lb is a branched lipid of Formula IIIc;
• Formula IIa branched linker structure:
• W is optional;
• W, if present, is an X1 linkage, N—C(O), N—C(O)O, or N—OC(O);
• wherein W is optionally substituted with D, which is an optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or heterocycle;
• each occurrence of (X)n is an independently selected —(CR1R2)n-;
• n of (X)n is 0 to 10;
• and T is optional and is an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or heterocycle and wherein T is optionally substituted;
• B is a carbon atom linked to L1 and L2 via respective G1 and G2;
• wherein G1 and G2 are independently selected from an X1;
• wherein each of G1 and G2 is independently optionally covalently bonded to B via an intervening (G)u group as B-(G)u-G1 or B-(G)u-G2, respectively;
• wherein (G)u is an independently selected —(CR1R2)u- wherein R1 and R2 are each independently:
• hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or heterocycle and u is 0 to 16;
• wherein G3 is optional and is selected from X1 and optionally covalently bonded to the B via an intervening (G)u group as B-(G)u-G3;
• L1 is a branched hydrocarbon of Formula IIIc;
• L2 is a hydrocarbon chain having 1 to 20 carbon atoms and 0 to 2 cis or trans double bonds or has the structure of Formula IIIc;
• L3 if present is hydrogen, a linear or branched hydrocarbon chain having 1 to 20 carbon atoms and 0 to 2 cis or trans double bonds or has the structure of Formula IIIc;
• Formula IIb ring structure:
• wherein the curved line represents a ring and E and K depict atoms that partially form the structure of the ring, which ring is a substituted or unsubstituted ring having 3 to 8 ring atoms;
• wherein at least one of L1, L2 and L3 are bonded to a single atom in the ring, optionally via a respective G1, G2 and G3, wherein each of G1, G2 and G3 is independently optionally covalently bonded to a respective one of the L1, L2 and L3 via an intervening (G)u, as G1-(G)u-L1, G2-(G)u-L2 or G3-(G)u-L3, respectively;
• wherein L1 and optionally L2 and/or L3 of Formula IIb have the structure of Formula IIIc;
• and
• wherein the A moiety is selected from one of:
• (i) ionizable cationic moieties selected from the group consisting of:
• (ii) permanently charged moieties selected from the group consisting of:
• (iii) ionizable anionic moieties selected from the group consisting of:
• or
• (iv) zwitterionic moieties selected from the group consisting of: