Cationic lipids for nucleic acid delivery and preparation thereof

Patent metadata

Field	Value
Publication number	US-11851389-B2
Application number	US-201716347995-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	Nov 8, 2016
Publication date	Dec 26, 2023
Grant date	Dec 26, 2023

Abstract

The present invention provides cationic lipids and lipid nanoparticle formulations comprising these lipids, alone or in combination with other lipids. These lipid nanoparticles may be formulated with nucleic acids to facilitate their intracellular delivery both in vitro and for therapeutic applications. The present invention also provides methods of chemical synthesis of these lipids, lipid nanoparticle preparation and formulation with nucleic acids.

First claim

What is claimed is:

1. A cationic lipid which is represented by the structure of formula (I), formula (II) or formula (IIIA), or salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof, wherein the structure of formula (I), formula (II) and formula (IIIA) is represented below:
Formula (I):

wherein
Y is O or NH;
T is C or S;
W is a bond or NH;
R 1 is selected from the group consisting of:
(a) NR 4 R 5 wherein R 4 and R 5 are each independently a C 1 -C 4 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a 5 or 6 membered heterocyclic or heteroaromatic ring, optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S; or NR 4 R 5 represent a guanidine group (—NHC(═NH)NH 2 );
(b) the side chain of histidine or arginine; and
(c) a 5 or 6 membered heterocyclic or heteroaromatic ring containing one or more heteroatoms selected from the group consisting of O, N and S;

R 2 and R 3 are selected from the group consisting of:
(a) C 10 -C 22 alkyl;
(b) C 10 -C 22 alkenyl;
(c) C 10 -C 22 alkynyl;
(d) C 4 -C 10 alkylene-Z— C 4 -C 22 alkyl; and
(e) C 4 -C 10 alkylene-Z— C 4 -C 22 alkenyl;

Z is —O—C(═O)—, —C(═O)—O— or —O—;
n is 0, 1, 2, 3, 4, 5 or 6;
m is 0 or 1;
p is 0 or 1; and
z is 0 or 2;
Formula (II):

wherein
A is

X′ is O or NH;
Y′ is O or NH;
provided that when A is

X′ and Y′ cannot both be O;
T is C or S;
W is a bond, O, NH or S;
R 1 is selected from the group consisting of:
(a) NR 4 R 5 wherein R 4 and R 5 are each independently a C 1 -C 4 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a 5 or 6 membered heterocyclic or heteroaromatic ring, optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S; or NR 4 R 5 represent a guanidine group (—NHC(═NH)NH 2 );
(b) the side chain of histidine or arginine; and
(c) a 5 or 6 membered heterocyclic or heteroaromatic ring containing one or more heteroatoms selected from the group consisting of O, N and S;

R 2 and R 3 are selected from the group consisting of:
(a) C 10 -C 22 alkyl;
(b) C 12 -C 22 alkenyl;
(c) C 10 -C 22 alkynyl;
(d) C 4 -C 10 alkylene-Z—C 4 -C 22 alkyl; and
(e) C 4 -C 10 alkylene-Z—C 4 -C 22 alkenyl;

Z is —O—C(═O)—, —C(═O)—O— or —O—;
n is 0, 1, 2, 3, 4, 5 or 6;
m is 0 or 1;
p is 0 or 1; and
z is 0 or 2;
Formula (IIIA):

wherein
X and Y are each independently O, N or NH, wherein X and Y cannot both be O;
each of R 1 , R 2 and R 3 is independently absent or a C 10 -C 22 alkyl, a C 10 -C 22 alkenyl or a C 10 -C 22 alkynyl, wherein the alkyl group is unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl;
n is an integer between 1 and 30; and
x is 0 or 2.

2. The cationic lipid according to claim 1 , which is represented by the structure of formula (I).

3. The cationic lipid according to claim 2 , wherein T is C or wherein R 1 is NR 4 R 5 .

4. The cationic lipid according to claim 2 , wherein p is 0, W is a bond and T is C, and the compound is represented by the structure of formula (Ia):

wherein R 1 , R 2 , R 3 , Y, m, n and z are as defined for formula (I).

5. The cationic lipid according to claim 4 , wherein R 1 is NR 4 R 5 , and the compound is represented by the structure of formula (Ia-1):

wherein R 2 , R 3 , R 4 , R 5 , Y, m, n and z are as defined for formula (I).

6. The cationic lipid according to claim 1 , which is represented by the structure of formula (II).

7. The cationic lipid according to claim 6 , which is represented by the structure of formula (IIa):

wherein R 1 , R 2 , R 3 , X′, T, W, n, m, p and z are as defined for formula (II).

8. The cationic lipid according to claim 7 , wherein p is 0, W is a bond and T is C, and the compound is represented by the structure of formula (IIa-1):

wherein R 1 , R 2 , R 3 , X′, n, m and z are as defined for formula (II).

9. The cationic lipid according to claim 8 , wherein R 1 is NR 4 R 5 , and the compound is represented by the structure of formula (IIa-2):

wherein R 2 , R 3 , R 4 , R 5 , X′, n, m and z are as defined for formula (II).

10. The cationic lipid according to claim 7 , wherein p is 1, m is 1, W is a bond and T is C, and the compound is represented by the structure of formula (IIa-3):

wherein R 1 is the side chain of histidine or arginine and R 2 , R 3 , X′, n and z are as defined for formula (II).

11. The cationic lipid according to claim 7 , wherein p is 0, R 1 is NR 4 R 5 , W is a bond, m is 0 and X′ is O, and the compound is represented by the structure of formula (IIa-4):

wherein R 2 , R 3 , R 4 , R 5 , n, and z are as defined for formula (II).

12. The cationic lipid according to claim 6 , which is represented by the structure of formula (IIb):

wherein R 1 , R 2 , R 3 , T, W, X′, Y′ n, m, p and z are as defined for formula (II), provided that when m is 1, Y′ is NH.

13. The cationic lipid according to claim 12 , wherein p is 0, W is a bond, T is C, and R 1 is NR 4 R 5 , and the compound is represented by the structure of formula (IIb-1):

14. The cationic lipid according to claim 1 , which is selected from the group consisting of:
2-(1,2-di((9Z,12Z)-octadeca-9,12-dien-1-yl)hydrazinyl)-N,N-dimethylethan-1-amine;
4-(1,2-di((9Z,12Z)-octadeca-9,12-dien-1-yl)hydrazinyl)-N,N-dimethylbutan-1-amine;
1-(4-(1,2-di((9Z,12Z)-octadeca-9,12-dien-1-yl)hydrazinyl)butyl)pyrrolidine;
N,N-dimethyl-4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)amino)butan-1-amine;
4-(dimethylamino)-N′—((Z)-octadec-9-en-1-yl)-N-((9Z,12Z)-octadeca-9,12-dien-1-yl)butanehydrazide;
4-(dimethylamino)-N-((9Z,12Z)-octadeca-9,12-dien-1-yl)-N-(((9Z,12Z)-octadeca-9,

Assignees

• Univ Ramot

Inventors

• Peer Dan
• Ramishetti Srinivas

Classifications

• C07C211/22 Primary

  containing at least two amino groups bound to the carbon skeleton · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title