Search

EP-4735418-A1 - LIPID COMPOUNDS FOR GENE DELIVERY AND USE THEREOF

EP4735418A1EP 4735418 A1EP4735418 A1EP 4735418A1EP-4735418-A1

Abstract

Disclosed herein are a class of lipid compounds that can be used in gene delivery, preparation thereof, and use thereof in gene delivery. Also disclosed herein are lipid nanoparticles comprising the lipid compound, gene delivery compositions comprising the lipid compound or the lipid nanoparticles. The lipid compounds, lipid nanoparticles and delivery system herein enable efficient complexation, protection, intracellular and targeted delivery and release of biomolecules such as oligonucleotides and nucleic acids in tissues and organs both in vitro and in vivo.

Inventors

  • XU, YUE
  • LI, BOWEN

Assignees

  • Li, Bowen

Dates

Publication Date
20260506
Application Date
20240701

Claims (20)

  1. A lipid compound of Formula (I) : or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R I , R II and R III are each independently selected from (A) a collection of groups comprising at least one ionizable tertiary amine moiety, (B) a collection of optionally substituted C 6 -C 25 aliphatic groups and optionally substituted 6-to 25-membered heteroaliphatic groups; preferably, one or two of R I , R II and R III is selected from (A) a collection of groups comprising at least one ionizable tertiary amine moiety.
  2. A lipid compound of Formula (I’) : or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R I , R II and R III are each independently selected from (A) a collection of groups comprising at least one ionizable tertiary amine moiety, (B) a collection of optionally substituted C 6 -C 25 aliphatic groups and optionally substituted 6-to 25-membered heteroaliphatic groups, and R II’ is hydrogen or C 1 -C 6 alkyl; preferably, one or two of R I , R II and R III is selected from (A) a collection of groups comprising at least one ionizable tertiary amine moiety.
  3. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the group comprising at least one ionizable tertiary amine moiety of the collection (A) has a carbon atom number of 3 to 11 and represented by Formula (Ia) : wherein R Ia is optionally substituted C 1 -C 6 alkylene, which alkylene is optionally substituted with 1, 2 or 3 substituents selected from -oxo (=O) , -OH, -SH or -NR Id R Id' , where R Id and R Id' are each independently hydrogen or C 1 -C 3 alkyl; R Ib and R Ic are each independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, which alkyl, alkenyl, and alkynyl are optionally substituted with 1, 2 or 3 substituents selected from -oxo (=O) , -OH, -SH or -NR Ie R Ie' , where R Ie and R Ie' are each independently hydrogen or C 1 -C 3 alkyl, or R Ib and R Ic together with the N atom to which they are attached form a 5-to 12-membered heterocycle comprising 1, 2 or 3 heteroatoms independently selected from N, O, and S, at least one of the heteroatoms is N, which heterocycle is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, -NO 2 and -OH..
  4. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the group comprising at least one ionizable tertiary amine moiety of the collection (A) has a carbon atom number of 3 to 11 and represented by Formula (Ia’) : wherein Ar is optionally substituted C 6 -C 10 arylene, which arylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1 -C 6 alkyl, -OH, -SH or -NR Id” R Id”' , where R Id” and R Id”' are each independently hydrogen or C 1 -C 3 alkyl; R Ib' and R Ic' are each independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, which alkyl, alkenyl, and alkynyl are optionally substituted with 1, 2 or 3 substituents selected from -oxo (=O) , -OH, -SH or -NR Ie” R Ie”' , where R Ie” and R Ie”' are each independently hydrogen or C 1 -C 3 alkyl, or R Ib' and R Ic' together with the N atom to which they are attached form a 5-to 12-membered heterocycle comprising 1, 2 or 3 heteroatoms independently selected from N, O, and S, at least one of the heteroatoms is N, which heterocycle is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, -NO 2 and -OH.
  5. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 4, wherein the collection (A) comprises the following groups comprising at least one ionizable tertiary amine moiety:
  6. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 4, wherein the collection (A) comprises the following groups comprising at least one ionizable tertiary amine moiety:
  7. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 4, wherein the collection (A) comprises the following groups comprising at least one ionizable tertiary amine moiety:
  8. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 7, wherein the collection (B) comprises optionally substituted C 6 -C 25 aliphatic groups and optionally substituted 6-to 25-membered heteroaliphatic groups, which aliphatic groups and heteroaliphatic groups are optionally comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 groups independently selected from -C=C-, -C≡C-, -NR m -, -NH-, -NH 2 , -OH, -OR n , -O-, -C (O) -, -C (OR o ) -, -C (O) O-, -SH, -SR p , -S-, -C (S) -, -C (SR q ) -, -C (S) O-, and -P (O) -groups, where R m , R n , R o , R p , and R q are each independently optionally substituted C 1 -C 14 aliphatic group.
  9. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 8, wherein the group of collection (B) optionally comprises at least one degradable moiety.
  10. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 9, wherein the degradable moiety is selected from -C (O) O-, -OC (O) -, -OC (O) O-, -S-S-, -C (O) NH-, -NHC (O) -, -NHC (O) O-, -NR 1 C (O) -, -C (O) NR 2 -, -NR 3 C (O) O-, -OP (O) OR 4 O-, -OCR 5 (OR 6 ) O-, -CR 7 (OR 8 ) O-, and -CH (OR 9 ) O-, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently optionally substituted C 1 -C 14 aliphatic group.
  11. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 10, wherein the collection (B) comprises the following groups:
  12. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 10, wherein the collection (B) comprises the following groups:
  13. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 10, wherein the collection (B) comprises the following groups:
  14. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 13, wherein R I , R II and R III satisfy the following conditions: R I is selected from the collection (A) , and R II and R III are selected from the collection (B) ; or R II is selected from the collection (A) , and R I and R III are selected from the collection (B) ; or R III is selected from the collection (A) , and R I and R II are selected from the collection (B) .
  15. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the lipid compound is selected from the compounds listed below: (Z) -6- ( (3- (dimethylamino) propanoyl) oxy) -7- (octadec-9-en-1-ylamino) -7-oxoheptyl dodecanoate (Z) -6- ( (3- (dimethylamino) propanoyl) oxy) -7- (octadec-9-en-1-ylamino) -7-oxoheptyl 2-hexyldecanoate (Z) -6- ( (4- (dimethylamino) butanoyl) oxy) -7- (octadec-9-en-1-ylamino) -7-oxoheptyl 2-hexyldecanoate (Z) -6- ( (5- (dimethylamino) pentanoyl) oxy) -7- (octadec-9-en-1-ylamino) -7-oxoheptyl 2-hexyldecanoate
  16. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the lipid compound is selected from the compounds listed in Table 1, 2, 3, and/or 4.
  17. A method for preparing the lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 16, comprising following synthetic route: wherein R I , R II and R III are defined as in any of claims 1 to 15; or following synthetic route: wherein, R I , R II , R II’ and R III are defined as in any of claims 1 to 15.
  18. The lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 16 for use in gene delivery.
  19. Use of the lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 16 in gene delivery.
  20. Use of the lipid compound or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof according to any of claims 1 to 16 in preparation of lipid nanoparticles.

Description

LIPID COMPOUNDS FOR GENE DELIVERY AND USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of PCT Application PCT/CN2023/105072, filed June 30, 2023. The entire content of the foregoing application is incorporated herein by reference. FIELD The present disclosure belongs to the field of gene loading and delivery and relates specifically to lipid compounds that can be used for gene delivery, preparation thereof and use thereof in gene delivery. The present disclosure also relates to lipid nanoparticles comprising the lipid compound, gene delivery compositions comprising the lipid compound or the lipid nanoparticles. BACKGROUND A large number of different types of nucleic acids are currently being developed as therapeutic agents for the treatment of a wide range of diseases. These include DNA and mRNA in gene therapy, plasmid-based interfering nucleic acids, small interfering nucleic acids for RNA interference (RNAi) , including siRNA, miRNA, antisense molecules, nucleases and aptamers. Effective nucleic acid drug delivery requires the intracellular delivery of therapeutic nucleic acid molecules to the target cells. In living organisms, naked nucleic acid molecules are broken down and removed by a large number of nucleases. Furthermore, due to the naturally negative electrical properties of nucleic acid molecules, it is difficult for them to directly penetrate negatively charged cell membranes and therefore special delivery systems are required to protect the nucleic acid molecules and facilitate their entry into the target cells. Lipid nanoparticles are currently the most effective form of carrier for nucleic acid drug delivery and have been validated in a number of marketed drugs, including the Covid-19 mRNA vaccine. Classical lipid nanoparticles are formed by encapsulation of nucleic acid molecules by four kinds of lipids such as ionizable lipids, cholesterol, neutral phospholipids and polyethylene glycol (PEG) lipids, wherein the ionizable lipid determines the efficiency of the lipid nanoparticles in delivering nucleic acid molecules in vitro and in vivo. The delivery of therapeutic nucleic acid molecules to the target is important for their therapeutic efficacy and this can often be hampered by the limited ability of ionizable lipids to reach the targeted cells and tissues. By expanding and optimizing the structure of the ionizable lipids is essential for access to the tissue cells targeted. The present disclosure relates to novel ionizable lipids that facilitate the targeted intracellular delivery of biologically active molecules. Examples of biologically active molecules for which effective targeting of patient tissues is often not achieved include (1) a wide range of proteins, including immunoglobulins; (2) polynucleotides, such as genomic DNA, cDNA or mRNA; (3) antisense polynucleotides; and (4) many small molecular weight compounds, whether synthetic or naturally occurring, such as peptide hormones and antibiotics. One of the fundamental challenges that medical practitioners are now facing is the large number of different types of nucleic acids that are currently being developed as therapeutic agents for the treatment of a wide range of diseases. These include DNA in gene therapy, plasmid-based small interfering nucleic acids (iRNA) for RNA interference (RNAi) , antisense molecules, nucleases, antagomir, microRNAs and aptamers. With the development of these nucleic acids, there is a widespread need to produce lipid formulations that are easy to prepare and can be easily delivered to target tissues. Despite advancements in developing new ionizable lipids that improve mRNA loading and delivery, significant challenges persist in designing new lipid structures. Traditional ionizable lipid synthesis is marked by a series of complex steps, including chemical protection and deprotection, catalyst use and removal, solvent exchange, and complicated purification processes. These time-consuming procedures necessitate customization for each synthetic reaction, limiting throughput and constraining the exploration of new lipid structures. Combinatorial chemistry is particularly valuable in the development of ionizable lipids by facilitating the creation of extensive libraries through systematic combinations of multiple building blocks. This approach allows researchers to quickly and efficiently generate diverse libraries of ionizable lipid  structures, which can then be screened for their capacity to encapsulate and effectively deliver mRNA to target cells. Through this high-throughput approach, the potential for discovering more efficient and less toxic ionizable lipids is vastly increased. However, the currently available methods using combinatorial chemistry are often limited in the structural diversity of the ionizable lipids they produce due to the two-dimensional nature of the reactions they employ. Combinatorial chemistry using multi-component reactions (MCR) is